Parkinson's drug pulled out in US over concerns of cardiac valvulopathy

US FDA recently announced voluntary withdrawal Parkinson’s disease drug Pergolide by manufacturers following reports of serious cardiac valvular damage. The products being withdrawn are PERMAX, marketed by Valeant Pharmaceuticals, and two generic versions of pergolide manufactured by Par and Teva.

Pergolide, an ergotamine derivative belonging to the dopamine receptor agonist class, is used in the treatment of Parkinson’s disease both as adjunctive therapy for patients with motor fluctuations, and as initial monotherapy. Pergolide was approved in 1988 and is used by a minority of Parkinson’s patients, an estimated 12000 to 25000.

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. In a 2004 Lancet article Van Camp and colleagues [Van Camp G, et al. Treatment of Parkinson's disease with pergolide and relation to restrictive valvular heart disease. Lancet April 10, 2004;363:1179-83] concluded that restrictive valvular cardiac disease is common in patients receiving pergolide for Parkinson's disease, and the underlying pathology was believed to be fibrotic changes in leaflets and subvalvular apparatus causing stiffening of the valves and distortion of their normal functioning In 2006, the warning was upgraded to a black box because of new data concerning risks of heart valve damage.

The recent FDA decision to take the drug off the market comes following two recent articles published in the
New England Journal of Medicine confirming the link between pergolide and valvular disease.

In the first study conducted by
Schade and colleagues treatment with pergolide for more than 6 months increased the relative risk for valvular heart disease by a factor of 7.1;patients with doses above 3 mg/day had substantially greater risks. The study also linked another dopamine agonist cabergoline (DOSTINEX) with valvular regurgitation; increasing the relative risk by a factor of 4.9. There were no cases attributed to bromocriptine or lisuride, two other ergot-derived dopamine agonists or to ropinirole or pramipexole, two newer non-ergot dopamine agonists.

In the other study
Zanettini and colleagues used an internationally accepted standard for abnormality on echocardiography to show that patients exposed to pergolide had significantly increased risks for mitral and aortic regurgitation, and cabergoline users had a significantly increased risk for aortic regurgitation, compared to controls. Patients taking other dopamine agonists did not have valve regurgitation.

The fact that only pergolide and cabergoline are associated with valvulopathy whereas the newer, non-ergot dopamine agonists (ropinirole and pramipexole) and the two other ergot dopamine agonists (bromocriptine and lisuride) do not appear to cause valve changes suggest that it is not the ergot molecular skeleton which is the pathogenic factor.
In 1997 the appetite-suppressant drug
Fenfluramine was withdrawn from the US market following similar reports of cardiac valvulopathy. Roth suggested that fenfluramine and, in particular, its active metabolite norfenfluramine is a potent agonist of 5-HT2B receptors. These receptors are plentiful in human cardiac valves and appear to be essential for normal cardiac development. Roth suggested that fenfluramine inappropriately stimulates 5-HT2B receptors causing proliferative valve disease.

The valvulopathy associated with pergolide is thought to be due to pergolide's action on 5-HT2B receptor of cardiac myocytes, causing proliferative valve disease by the same mechanism as
ergotamine, methysergide, fenfluramine, and other serotonin 5-HT2B agonists, including serotonin itself when elevated in the blood in carcinoid syndrome.

For clinicians who have patient taking Pergolide FDA recommends gradual reduction of the dose before the drug is stopped altogether, since rapid discontinuation of all dopamine agonist can be dangerous. If continued therapy with a dopamine agonist is necessary another dopamine agonist should be substituted for pergolide.