Transcript Slide 1

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The products being withdrawn are Permax, the trade name for pergolide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.