Across Specialties
R H E U M AT O L O G Y N E W S • S e p t e m b e r 2 0 0 7
Black Box Heart Warning Strengthened for TZDsThe labeling change extends to the TZD combination
heart failure. After treatment with these
products is initiated or after the dose is in-
drugs Avandaryl, Avandamet, and Duetact.
creased, patients should be carefully ob-
the study, overnight hospitalizations for
heart failure were reported in nearly 10%
B Y E L I Z A B E T H M E C H C AT I E
data from meta-analyses of the rosiglita-
risk for myocardial ischemia for the type
are diagnosed with heart failure should re-
verse event that was “more marked” in
The labels of all thiazolidinediones 2 diabetes therapy. The agency is cur- ceive appropriate treatment for heart fail- patients taking insulin at baseline and in
rently reviewing similar pooled data from
tion of the TZD “should be considered.”
FDA’s concerns that despite the warnings
and information already listed in the drug
that thiazolidinediones (TZDs) may “cause
NYHA class I or II heart failure, who were
or exacerbate congestive heart failure in
some patients,” according to the FDA. The FDA will continue to
ters requesting the labeling change in May. monitor postmarketing reports of heart failure, and a review of rosiglitazone
“will consider further regulatory action
and the possible increased
mation becomes available.” The agency’s
(HF) in the warnings and precautions sec-
risk of MI is ongoing.
review of rosiglitazone and the possible in-
tions, but the labeling is being strength-
warning advises health care professionals
rosiglitazone’s cardiovascular safety.
to observe patients carefully for the signs
www.fda.gov/medwatch/safety/2007/safety
heart failure is “separate” from the con-
excessive, rapid weight gain, shortness of
and increases in heart failure medications
07.htm#rosi_pio. Adverse or serious events
cerns over the increased MI risk associat-
associated with TZDs should be reported to
ed with rosiglitazone, which was the sub-
the FDA’s MedWatch program at 800-332-
tion of rosiglitazone or pioglitazone, or
Brian Marson, assistant news editor for
drugs, is contraindicated in patients with
Elsevier’s “The Pink Sheet,” contributed to
New York Heart Association class III or IV
FDA Advisers Decide Rosiglitazone Should Stay, With Warnings
B Y A L I C I A A U LT
dione on the market,” said Dr. Schade. If rosiglitazone
move is not so clear. There is division within the FDA over
Associa te Editor, Practice Trends
was withdrawn, the panel might later regret having tak-
whether the drug should stay on the market.
en away an option, he said, noting that the other thiazo-
Dr. David Graham, an associate director for science
G A I T H E R S B U R G , M D. — The oral diabetes agent
lidinedione currently available—pioglitazone (Actos)—
and medicine in the Office of Surveillance and Epi-
rosiglitazone should remain on the market, albeit with
also has some safety concerns, notably a signal of an
demiology, said that rosiglitazone should be withdrawn.
some warnings about an increased cardiac ischemia risk,
Dr. Graham, who sounded the alarm about Merck’s ro-
said a majority of the members of a joint meeting of the
In a statement, the American Association of Clinical
fecoxib (Vioxx) in 2004, said that rosiglitazone may
Food and Drug Administration’s Endocrinologic and
Endocrinologists (AACE) said that it welcomed the FDA
have been responsible for 66,000-200,000 excess cardio-
Metabolic Drugs and Drug Safety and Risk Management
panel’s recommendation that rosiglitazone stay on the
vascular deaths, nonfatal heart attacks, and strokes from
market, but that “at the same time, AACE recognizes the
The combined panels voted 20-3 that rosiglitazone
strong statement of the panel that the drug may increase
The drug offers no unique short-term benefits for
(Avandia) increases ischemic risk, and 22-1 that the drug,
glycemic control and has not demonstrated long-term re-
a thiazolidinedione, should stay on the U.S. market.
However, said AACE, “physicians can continue to treat
ductions in micro- or macrovascular complications, said
“The committee felt relatively uniformly that there was
persons with diabetes who are well controlled with Avan-
some risk associated with the use of rosiglitazone in cer-
dia, knowing that it has been shown useful and effective
His boss, Office of Surveillance and Epidemiology di-
tain diabetic patients,” panel chairman Dr. Clifford Rosen
rector Dr. Gerald Dal Pan, agreed that the “balance of the
said in a postmeeting briefing with reporters.
The expert advisers drew their conclusions primarily
benefits and risks do not favor rosiglitazone.”
Dr. Rosen said that panelists were most concerned
from three meta-analyses of some 40 studies: one by
But Dr. Robert Meyer, director of the Center for Drug
about increased risk of ischemia, heart attack, and death
Avandia manufacturer GlaxoSmithKline (GSK), another
Evaluation and Research’s Office of Drug Evaluation II,
in patients taking insulin along with rosiglitazone. Sev-
by the FDA’s biostatisticians, and the third by Dr. Steven
which oversees the approval of endocrinology drugs, said,
eral committee members suggested a contraindication or
Nissen, medical director of the Cleveland Clinic (N.
“there is a fundamental disagreement within CDER.” He
added, however, “I do not have an opinion on what reg-
A few others suggested a black box warning on in-
Dr. Nissen was a nonvoting consultant, and his data
ulatory action should be taken on Avandia.”
creased potential for heart failure, for which there is al-
were barely discussed, because the “FDA analysis of the
The agency will “move this forward as quickly as we
ready a warning. Several panelists also said that patients
data, including patient level data [provided by GSK], is
can,” Dr. Douglas Throckmorton, CDER deputy direc-
with advanced cardiovascular disease or who regularly
more robust than would be possible for an analysis uti-
tor, told reporters after the meeting. “Obviously, this is a
used nitrates should probably not take rosiglitazone.
lizing study-level data alone” according to the FDA’s
“These are the people for whom clinicians are going to
GSK said it would continue to provide the FDA with
have to think twice before prescribing [rosiglitazone],”
The trials in the meta-analyses included mostly short-
information. “We welcome this decision as positive for
said Dr. Rosen, a senior staff scientist at the Maine Cen-
term data. GSK also provided the FDA with longer-term
patients,” said Dr. Ronald Krall, GSK chief medical offi-
ter for Osteoporosis, St. Joseph Hospital, Bangor.
data from three outcome studies and several epidemiol-
cer, in a statement after the meeting.
An endocrinologist on the committee, Dr. David S.
Schade of the University of New Mexico, Albuquerque,
Meta-Analyses
argued before the panel voted that Avandia should stay
Dissension Within FDA
The FDA convened the joint panel primarily to assess the
The FDA usually follows its advisory panels’ advice,
Clinicians “absolutely . need to have a thiazolidine-
though not always. With rosiglitazone, the agency’s next
Bio data: Dr. Pratap N Mukhopadhyaya --------------------------------------------------------------------------------------------------- Dr. Pratap Narayan Mukhopadhyaya PERSONAL DETAILS • Place of birth: Varanasi, Uttar Pradesh, INDIA ACADEMIC QUALIFICATIONS B.Sc (Hons) [ Botany , Zoology Chemistry] Burdwan University, West Bengal – Year 1988 M.Sc Plant Sciences [
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