GlaxoSmithKline (GSK) late last month notified health care professionals
that it was strengthening product label warnings advising against the use of
paroxetine (Paxil, Paxil CR) by women who are pregnant.
The company cited newly analyzed data from a retrospective epidemiologic
study of major congenital malformations in infants, saying that"
preliminary results suggest an increase in the risk of congenital
malformations associated with the use of paroxetine as compared to other
Changes in the drug's labeling are being made after consultation with the
U.S. Food and Drug Administration (FDA).
Current FDA-approved labeling lists paroxetine as a pregnancy Category C
drug. Category C is defined as drugs with "no adequate and
well-controlled studies in humans to determine the effect on the fetus."
Current labeling reminds prescribers that paroxetine during pregnancy should
be used only if the potential benefit justifies the potential risk.
Information will be added to the product label indicating that of 3,581
pregnant women exposed to paroxetine or other antidepressants during the first
trimester, use of paroxetine, compared with other antidepressants, was
associated with an "increased risk of overall major congenital
Specifically, women who took paroxetine were 2.2 times more likely to give
birth to an infant with a major congenital malformation and 2.08 times more
likely to give birth to an infant with a cardiovascular malformation than
women on other antidepressants. Of 14 infants with a major congenital
malformation born to women taking paroxetine, 10 of those with cardiovascular
malformations had ventricular septal defects.
The new labeling goes on to note that a separate study based on the Swedish
Medical Birth Registry "evaluated 4,291 infants exposed to SSRIs in
early pregnancy. This study reported no increased risk for overall major
malformations in 708 infants born to women with paroxetine exposure early in
In the company's "Dear Healthcare Provider" letter regarding
the new labeling, GSK said that "it is important to note that because
the GSK study was designed to evaluate the relative risk of
congenital malformations in infants born to women exposed to antidepressants,
the study did not include a comparison to infants who were not exposed to any
antidepressant. Therefore, these data should be viewed within the context of
the overall prevalence of congenital malformations in the general population,
which is estimated in the U.S. to be approximately 3 percent for any
malformation, and approximately 1 percent for cardiovascular malformations
GSK reviewed other epidemiological studies of SSRI exposure during
pregnancy in its "Dear Healthcare Provider" letter, as well as
several case-control studies. In addition, it cited the National Birth Defects
Prevention Study of infants delivered from 1997 through 2001.
In that study, women who took any SSRI were more likely than those who were
not exposed to have an infant with omphalocele.
The strongest effect was reported in that study to be with paroxetine,
which accounted for 36 percent of all exposures to an SSRI. Infants born to
mothers taking paroxetine during the first trimester were found to be 6.3
times more likely to have an omphalocele compared with infants born to mothers
who took no SSRIs. An association was also found between SSRI exposure and
infants being born with craniosynostosis.
GSK concluded, "The differences in the results from the available
studies and the diversity in type of abnormalities recently reported makes it
difficult to definitively conclude a causal relationship for any particular
congenital abnormality with paroxetine."
The company, in cooperation with FDA requests, is conducting additional
epidemiologic studies "to more fully understand these preliminary
The FDA's MedWatch report on paroxetine and congenital abnormalities
and GSK's "Dear Healthcare Provider" letter are posted at<www.fda.gov/medwatch/safety/2005/safety05.htm#Paxil2>.▪