Healthy Skepticism Library item: 2598

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Publication type: news

Reuters .
Glaxo adds birth defect caution to Paxil label
Yahoo News ( via Reuters) 2005 Sep 27
http://news.yahoo.com/s/nm/20050927/hl_nm/glaxosmithkline_paxil_dc

Abstract:

GlaxoSmithKline
Three Franklin Plaza
3F0615
P.O. Box 7404
Philadelphia, PA 19101
Tel. 214 751 4000
www.gsk.com
Date
IMPORTANT PRESCRIBING INFORMATION
Dear Healthcare Professional:
GlaxoSmithKline (GSK) would like to advise you that it is changing the Pregnancy
subsection of the PRECAUTIONS section in the labels for PAXIL® (paroxetine HCl)
and PAXIL CR® (paroxetine HCl) Controlled-Release Tablets.
SUMMARY
• Paroxetine currently carries a Category C pregnancy precaution, indicating that
there are no adequate and well-controlled studies in humans to determine the
effect of paroxetine on the fetus. Labeling states that the drug should be used
during pregnancy only if the potential benefit justifies the potential risk to the
fetus. The label also currently includes information related to possible
nonteratogenic effects, including symptoms and complications observed in
neonates exposed to paroxetine in the third trimester of pregnancy.
• GSK recently conducted a retrospective epidemiologic study of major congenital
malformations in infants born to women taking antidepressants during the first
trimester of pregnancy. Preliminary results suggest an increase in the risk of
congenital malformations associated with the use of paroxetine as compared to
other antidepressants. The types of congenital malformations, which were most
commonly cardiovascular, were reflective of those seen in the general population.
The most common cardiovascular malformations observed in the study were
ventricular septal defects.
• The preliminary results of this study and recent abstracts published by Alwan &
Wogelius differ from previous epidemiologic studies, making it difficult to
conclude whether a causal relationship exists. For example, data from the
Swedish Medical Birth Registry, one of the largest available birth registries, have
not provided evidence for an increased risk of major malformations with SSRI
medications, including paroxetine.
• GSK believes it is important to draw your attention to these recent findings, and is
voluntarily adding this information to the paroxetine label. GSK will post the
September 2005
results of this study to its Clinical Trial Register where it can be read by anyone
with Internet access. The website is http://ctr.gsk.co.uk/welcome.asp.
RECOMMENDATIONS
• As with all Pregnancy Category C drugs, health care providers are advised to
carefully weigh the potential risks and benefits of using paroxetine therapy in
women during pregnancy. It is recommended that health care providers discuss
these latest findings, described in more detail below, as well as treatment
alternatives, with their patients.
• If you choose to discontinue paroxetine in a patient, please refer to the
Discontinuation of Treatment with PAXIL/PAXIL CR subsection of the
PRECAUTIONS section in the labeling for further information.
• Paroxetine should be used during pregnancy only if the potential benefit justifies
the potential risks to the fetus.
Please see below for the full text of the amended PRECAUTIONS (new text has been
underlined). Complete copies of the revised package inserts for PAXIL and PAXIL CR
are enclosed.
PAXIL CR:
PRECAUTIONS
Pregnancy: Teratogenic Effects: Pregnancy Category C.
There are no adequate and well controlled studies in pregnant women. A recent
retrospective epidemiological study of 3,581 pregnant women exposed to
paroxetine or other antidepressants during the 1st trimester suggested an increased
risk of overall major congenital malformations for paroxetine compared to other
antidepressants (OR 2.20; 95% confidence interval 1.34-3.63). There was also an
increased risk for cardiovascular malformations for paroxetine compared to other
antidepressants (OR 2.08; 95% confidence interval 1.03-4.23); 10 out of 14 infants
with cardiovascular malformations had ventricular septal defects. 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 in early
pregnancy.
Reproduction studies were performed at doses up to 50 mg/kg/day in rats and 6
mg/kg/day in rabbits administered during organogenesis. These doses are
approximately 8 (rat) and 2 (rabbit) times the MRHD on an mg/m2 basis. These
studies have revealed no evidence of teratogenic effects. However, in rats, there
was an increase in pup deaths during the first 4 days of lactation when dosing
occurred during the last trimester of gestation and continued throughout lactation.
This effect occurred at a dose of 1 mg/kg/day or approximately one-sixth of the
MRHD on an mg/m2 basis. The no-effect dose for rat pup mortality was not
determined. The cause of these deaths is not known. Paroxetine should be used
during pregnancy only if the potential benefit justifies the potential risk to the fetus.
PAXIL:
PRECAUTIONS
Pregnancy: Teratogenic Effects: Pregnancy Category C.
There are no adequate and well controlled studies in pregnant women. A recent
retrospective epidemiological study of 3,581 pregnant women exposed to
paroxetine or other antidepressants during the 1st trimester suggested an increased
risk of overall major congenital malformations for paroxetine compared to other
antidepressants (OR 2.20; 95% confidence interval 1.34-3.63). There was also an
increased risk for cardiovascular malformations for paroxetine compared to other
antidepressants (OR 2.08; 95% confidence interval 1.03-4.23); 10 out of 14 infants
with cardiovascular malformations had ventricular septal defects. 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 in early
pregnancy.
Reproduction studies were performed at doses up to 50 mg/kg/day in rats and 6
mg/kg/day in rabbits administered during organogenesis. These doses are
equivalent to 9.7 (rat) and 2.2 (rabbit) times the maximum recommended human
dose (MRHD) for major depressive disorder, social anxiety disorder, GAD, and
PTSD (50 mg) and 8.1 (rat) and 1.9 (rabbit) times the MRHD for OCD, on an
mg/m2 basis. These studies have revealed no evidence of teratogenic effects.
However, in rats, there was an increase in pup deaths during the first 4 days of
lactation when dosing occurred during the last trimester of gestation and continued
throughout lactation. This effect occurred at a dose of 1 mg/kg/day or 0.19 times
(mg/m2) the MRHD for major depressive disorder, social anxiety disorder, GAD,
and PTSD; and at 0.16 times (mg/m2) the MRHD for OCD. The no-effect dose for
rat pup mortality was not determined. The cause of these deaths is not known.
Paroxetine should be used during pregnancy only if the potential benefit justifies
the potential risk to the fetus.
BACKGROUND
GSK conducted a retrospective epidemiologic study of major congenital malformations
in infants born to women taking antidepressants during the first trimester of pregnancy.
A preliminary analysis has recently been conducted which yielded adjusted odds ratios of
2.20 (95% Confidence interval [CI]: 1.34-3.63) for congenital malformations as a whole,
and 2.08 (CI: 1.03-4.23) for cardiovascular malformations alone, for paroxetine as
compared to the other antidepressants in the database. The prevalences of congenital
malformations as a whole and cardiovascular malformation alone were approximately 4%
and 2%, respectively. Of the cardiovascular malformations reported in infants whose
mothers were dispensed paroxetine, the majority were ventricular septal defects.
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 US to be approximately 3% for any malformation and approximately 1% for
cardiovascular malformations alone (Honein 1999).
Previous epidemiological studies of pregnancy outcome following first trimester
exposure to selective serotonin reuptake inhibitors (SSRIs), including paroxetine, have
not provided evidence for an increased risk of major malformations for SSRI
medications. In the most recent publication based on the Swedish Medical Birth Registry
(Hallberg 2005), which unlike the GSK study above, included a comparison to infants not
exposed to antidepressants, data on 4,291 infants born to mothers exposed to SSRIs in
early pregnancy demonstrated an overall prevalence of 2.9% for congenital
malformations, which the authors concluded did not differ from the expected rate of 3.5%
among unexposed infants. Of 708 exposures to paroxetine in this registry, the prevalence
of malformations was 3.4%.
In addition to the data by Hallberg et al, there are three published reports of small,
epidemiologic case-control studies based on prospectively gathered data in women
exposed to paroxetine during their first trimester (Kulin, 1998; Unfred, 2001; Diav-Citrin,
2002). The number of paroxetine-exposed pregnancies reported in the three studies
ranged from 89 to 97, and all studies found no major teratogenic risk. A small study (19
paroxetine-exposed pregnancies) based on medical records review found congenital
anomaly rates in accord with the general population (Hendrick, 2003).
More recently, Alwan et al (2005) have reported data obtained from the National Birth
Defects Prevention Study of infants delivered from 1997-2001. Adjusted analyses
showed that women who took an SSRI were more likely than those who were not
exposed to have an infant with omphalocele (n=161) (odds ratio [OR] 3.0, CI 1.4-6.1).
The strongest effect was reported to be with paroxetine, which accounted for 36% of all
SSRI exposures (OR 6.3, CI 2.0-19.6). The authors also found an association of
exposure to any SSRI and having an infant with craniosynostosis (n=372) (OR 1.8, CI
1.0-3.2).
A second abstract, from Wogelius et al, just presented at the 21st International Conference
on Pharmacoepidemiology and Therapeutic Risk Management (August 21-24, 2005),
reported an adjusted OR of 1.4 (CI 1.1-1.9) for congenital malformations overall and 1.6
(CI 1.0-2.6) for congenital cardiac malformations in women who redeemed a prescription
for SSRIs (paroxetine-specific data were not presented) from 30 days before conception
to the end of the first trimester compared to women with no SSRI prescriptions during
this period.
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, however GSK
believes it is important to draw your attention to the most recent findings. GSK is
conducting additional epidemiologic studies to more fully understand these preliminary
findings.
PAXIL is indicated for the treatment of major depressive disorder, obsessive-compulsive
disorder, panic disorder, social anxiety disorder, generalized anxiety disorder, and
posttraumatic stress disorder; PAXIL CR is indicated for the treatment of major
depressive disorder, panic disorder, social anxiety disorder, and premenstrual dysphoric
disorder.
The medical community can further our understanding of PAXIL and PAXIL CR by
reporting adverse events to GlaxoSmithKline at 1-888-825-5249 or to the FDA
MEDWATCH program by phone at 1-800-FDA-1088, by FAX at 1-800-FDA-0178, by
modem at 1-800-FDA-7737 or by mail:
MEDWATCH HF-2
FDA
5600 Fisher’s Lane
Rockville, MD 20857
GlaxoSmithKline encourages you to familiarize yourself with these revisions to labeling.
If you have any questions about the new information, please contact our Customer
Response Center at 1-888-825-5249. You can find other useful information related to
this issue as well as to clinical trials involving other GSK products at our Clinical Trial
Registry website (http://ctr.gsk.co.uk/welcome.asp).
Sincerely,
Regional Medical Director
Worldwide Development
GlaxoSmithKline

Keywords:
antidepressant Paxil congenital birth defects

Notes:

Ralph Faggotter’s Comments: The more we learn about Paxil, the more doubtful we are about it.
this study found that “…infants born to women who took Paxil were more likely to be born with an abnormality than babies born to women who took another antidepressant.”
At least the company, GlaxoSmithKline, was honest enough to publish the results of this damaging study.
Drug companies are not always this forthright!
See under ‘Official Abstract’ above for GSK’s ‘dear doctor’ letter.

Full text:

Tue Sep 27, 6:11 PM ET

WASHINGTON (Reuters) – GlaxoSmithKline Plc is alerting physicians about a study suggesting the company’s antidepressant Paxil may be linked more often to birth defects than similar drugs, U.S. regulators said on Tuesday.

The British drug maker, in a letter to physicians, said it was adding the information to the prescribing instructions on Paxil’s label. Glaxo said it was difficult to tell if Paxil caused the defects, most of which were cardiovascular, in infants born to women who took the drug while pregnant.

“Preliminary results suggest an increase in the risk of congenital malformations associated with the use of (Paxil) as compared to other antidepressants,” the company’s letter to physicians said.

“The preliminary results of this study and recent abstracts … differ from previous epidemiologic studies, making it difficult to conclude whether a causal relationship exists,” it said.

Physicians should “carefully weigh the potential risks and benefits of using paroxetine (Paxil) therapy in women during pregnancy and … discuss these findings as well as treatment alternatives with their patients,” the FDA said.

The new study examined records of infants born to 3,581 women who took Paxil or other antidepressants during the first trimester of pregnancy.

A preliminary analysis found infants born to women who took Paxil were more likely to be born with an abnormality than babies born to women who took another antidepressant, Glaxo said. Overall, 4 percent of babies had some type of malformation. The typical rate for birth defects among infants is about 3 percent.

“GSK is conducting additional epidemiologic studies to more fully understand these preliminary findings,” the company said.

An earlier study of 4,291 infants found no increased risk of birth defects for women who took Paxil early in pregnancy, Glaxo said.

Glaxo’s letter to doctors is available online at http://www.fda.gov/medwatch/safety/2005/safety05.htm#Paxil2.