Paxil_letter_e3

GlaxoSmithKline
IMPORTANT PRESCRIBING INFORMATION
In September, 2005, GlaxoSmithKline (GSK) wrote to you regarding changes to thePregnancy subsection of the PRECAUTIONS section in the labels for PAXIL®(paroxetine HCl) and PAXIL CR® (paroxetine HCl) Controlled-Release Tablets. Theserevisions were in response to preliminary data from a GSK-sponsored epidemiologicstudy of major congenital malformations in infants born to women taking antidepressantsduring the first trimester of pregnancy, which suggested an increased risk of congenitalmalformations with maternal exposure to paroxetine.
Updated analyses from this study (based on a larger cohort of pregnant women taking
antidepressants), together with new data from another study utilizing a large medical
birth registry, have now become available. On the basis of these new data, GSK is
making further revisions to the labels for PAXIL® and PAXIL CR®, including
revision of the pregnancy precaution from Pregnancy Category C to Pregnancy
Category D (indicative of positive evidence of human fetal risk) as well as placement
of the usage in pregnancy language in the WARNINGS section of the label.
• Updated data from a GSK-sponsored, retrospective, U.S. epidemiologic study of major malformations following maternal exposure to antidepressants in the first
trimester showed a trend towards a 1.5-fold increased risk for cardiovascular
malformations for paroxetine compared to other antidepressants (whereas the
preliminary analysis showed a statistically significant increase in risk for
cardiovascular malformations). The most common cardiovascular malformations
observed among paroxetine-exposed infants were ventricular septal defects. This
study showed a statistically significant increased overall risk of major congenital
malformations (inclusive of the cardiovascular defects) in infants exposed to
paroxetine compared to other antidepressants. GSK has posted the 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
• A new study of delivery outcome following maternal use of SSRI antidepressants in early pregnancy has been conducted utilizing the Swedish national registry
data. This study has reported a 2-fold increased risk of cardiac defects
(contributed mainly by ventricular septal defects [VSD] and atrial septal defects
[ASD]) in infants exposed to paroxetine, compared with the general population.
Unlike the U.S. epidemiologic study mentioned above, this study found no
increase in the risk of overall congenital malformations after maternal use of
paroxetine -- an observation consistent with previous published analyses of these
registry data (cited in the previous version of the Prescribing Information), which
found no evidence for an increased overall risk of major malformations withmaternal exposure to SSRI medications, including paroxetine.
• It is not clear if the findings from these studies represent a true causal association with maternal paroxetine exposure. However, the data to date indicate that theindividual risk of a mother having an infant with a cardiac defect followingmaternal paroxetine exposure is approximately 1/50, compared with an expectedrate for such defects of approximately 1/100 infants in the general population. Ingeneral, septal defects can range from those that are symptomatic and may requiresurgery to those that are asymptomatic and may resolve spontaneously.
• GSK believes it is important to draw your attention to these recent findings, and is voluntarily adding details of these studies to the paroxetine label. On the basis ofthese data, it is considered appropriate at the current time to revise the pregnancyprecaution to Pregnancy Category D.
RECOMMENDATIONS
• If a patient becomes pregnant while taking paroxetine, she should be advised of the potential harm to the fetus. Unless the benefits of paroxetine to the motherjustify continuing treatment, consideration should be given to either discontinuingparoxetine therapy or switching to another antidepressant in these cases.
• If you choose to discontinue paroxetine in a patient, please refer to the Discontinuation of Treatment with PAXIL/PAXIL CR subsection of thePRECAUTIONS section in the labeling for further information.
• For women who intend to become pregnant or are in their first trimester of pregnancy, paroxetine should only be initiated after consideration of the otheravailable treatment options.
Please see below for the full text of the amended WARNINGS (new text has been
underlined). Complete copies of the revised package inserts for PAXIL and PAXIL CR
are enclosed.
WARNINGSUsage in Pregnancy: Teratogenic Effects: Epidemiological studies have shown that infants born to women who had firsttrimester paroxetine exposure had an increased risk of cardiovascularmalformations, primarily ventricular and atrial septal defects (VSDs and ASDs). Ingeneral, septal defects range from those that are symptomatic and may requiresurgery to those that are asymptomatic and may resolve spontaneously. If a patientbecomes pregnant while taking paroxetine, she should be advised of the potential harm to the fetus. Unless the benefits of paroxetine to the mother justify continuing
treatment, consideration should be given to either discontinuing paroxetine therapy
or switching to another antidepressant (see PRECAUTIONS: Discontinuation of
Treatment with PAXIL CR). For women who intend to become pregnant or are in
their first trimester of pregnancy, paroxetine should only be initiated after
consideration of the other available treatment options.
A study based on Swedish national registry data evaluated infants of 6, 896 womenexposed to antidepressants in early pregnancy (5,123 women exposed to SSRIs;including 815 for paroxetine). Infants exposed to paroxetine in early pregnancy hadan increased risk of cardiovascular malformations (primarily VSDs and ASDs)compared to the entire registry population (OR 1.8; 95% confidence interval 1.1-2.8). The rate of cardiovascular malformations following early pregnancyparoxetine exposure was approximately 2% vs. 1% in the entire registry population.
Among the same paroxetine exposed infants, an examination of the data showed noincrease in the overall risk for congenital malformations.
A separate retrospective cohort study using U.S. United Healthcare data evaluated5,956 infants of mothers dispensed paroxetine or other antidepressants during thefirst trimester (n=815 for paroxetine). This study showed a trend towards anincreased risk for cardiovascular malformations for paroxetine compared to otherantidepressants (OR 1.5; 95% confidence interval 0.8-2.9). The prevalence ofcardiovascular malformations following first trimester dispensing was 1.5% forparoxetine vs. 1% for other antidepressants. Nine out of 12 infants withcardiovascular malformations whose mothers were dispensed paroxetine in the firsttrimester had VSDs. This study also suggested an increased risk of overall majorcongenital malformations (inclusive of the cardiovascular defects) for paroxetinecompared to other antidepressants (OR 1.8; 95% confidence interval 1.2-2.8). Theprevalence of all congenital malformations following first trimester exposure was4% for paroxetine vs. 2% for other antidepressants.
Animal Findings: 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.
Nonteratogenic Effects: Neonates exposed to PAXIL CR and other SSRIs orserotonin and norepinephrine reuptake inhibitors (SNRIs), late in the third trimesterhave developed complications requiring prolonged hospitalization, respiratorysupport, and tube feeding. Such complications can arise immediately upondelivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia,hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constantcrying. These features are consistent with either a direct toxic effect of SSRIs andSNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, insome cases, the clinical picture is consistent with serotonin syndrome (seeWARNINGS—Potential for Interaction With Monoamine Oxidase Inhibitors).
There have also been postmarketing reports of premature births in pregnant women exposed to paroxetine or other SSRIs.
When treating a pregnant woman with paroxetine during the third trimester, the physician should carefully consider the potential risks and benefits of treatment (seeDOSAGE AND ADMINISTRATION).
WARNINGSUsage in Pregnancy: Teratogenic Effects: Epidemiological studies have shown that infants born to women who had first
trimester paroxetine exposure had an increased risk of cardiovascular
malformations, primarily ventricular and atrial septal defects (VSDs and ASDs). In
general, septal defects range from those that are symptomatic and may require
surgery to those that are asymptomatic and may resolve spontaneously. If a patient
becomes pregnant while taking paroxetine, she should be advised of the potential
harm to the fetus. Unless the benefits of paroxetine to the mother justify continuing
treatment, consideration should be given to either discontinuing paroxetine therapy
or switching to another antidepressant (see PRECAUTIONS: Discontinuation of
Treatment with PAXIL CR). For women who intend to become pregnant or are in
their first trimester of pregnancy, paroxetine should only be initiated after
consideration of the other available treatment options.
A study based on Swedish national registry data evaluated infants of 6,896 womenexposed to antidepressants in early pregnancy (5,123 women exposed to SSRIs;including n=815 for paroxetine). Infants exposed to paroxetine in early pregnancyhad an increased risk of cardiovascular malformations (primarily VSDs and ASDs)compared to the entire registry population (OR 1.8; 95% confidence interval 1.1-2.8). The rate of cardiovascular malformations following early pregnancyparoxetine exposure was approximately 2% vs. 1% in the entire registry population.
Among the same paroxetine exposed infants, an examination of the data showed noincrease in the overall risk for congenital malformations.
A separate retrospective cohort study using U.S. United Healthcare data evaluated5,956 infants of mothers dispensed paroxetine or other antidepressants during thefirst trimester (n=815 for paroxetine). This study showed a trend towards anincreased risk for cardiovascular malformations for paroxetine compared to otherantidepressants (OR 1.5; 95% confidence interval 0.8-2.9). The prevalence ofcardiovascular malformations following first trimester dispensing was 1.5% forparoxetine vs. 1% for other antidepressants. Nine out of 12 infants with cardiovascular malformations whose mothers were dispensed paroxetine in the firsttrimester had VSDs. This study also suggested an increased risk of overall majorcongenital malformations (inclusive of the cardiovascular defects) for paroxetinecompared to other antidepressants (OR 1.8; 95% confidence interval 1.2-2.8). Theprevalence of all congenital malformations following first trimester exposure was4% for paroxetine vs. 2% for other antidepressants.
Animal Findings: 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.
Nonteratogenic Effects: Neonates exposed to PAXIL and other SSRIs orSNRIs, late in the third trimester have developed complications requiring prolongedhospitalization, respiratory support, and tube feeding. Such complications can ariseimmediately upon delivery. Reported clinical findings have included respiratorydistress, cyanosis, apnea, seizures, temperature instability, feeding difficulty,vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness,irritability, and constant crying. These features are consistent with either a directtoxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. Itshould be noted that, in some cases, the clinical picture is consistent with serotoninsyndrome (see WARNINGS—Potential for Interaction With Monoamine OxidaseInhibitors).
There have also been postmarketing reports of premature births in pregnant women exposed to paroxetine or other SSRIs.
When treating a pregnant woman with paroxetine during the third trimester, the physician should carefully consider the potential risks and benefits of treatment (seeDOSAGE AND ADMINISTRATION).
BACKGROUND
GSK recently wrote to healthcare professionals advising of findings from a retrospective,U.S. epidemiologic study of major congenital malformations in infants born to 3,581women dispensed antidepressants during the first trimester of pregnancy. A preliminaryanalysis of these data 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) forcardiovascular malformations alone, for paroxetine as compared to the otherantidepressants in the database.
This retrospective cohort study, which used U.S. United Health Care data, was recentlyupdated to include an extended study population, now comprising 5,956 infants born to5,791 women dispensed antidepressants during the first trimester. The updated analysisshowed a trend towards an increased risk for cardiovascular malformations for paroxetinecompared to other antidepressants (OR 1.54; 95% confidence interval 0.81-2.92); nineout of 12 infants with cardiovascular malformations born to mothers who were dispensedparoxetine (and no other antidepressants) had a VSD. The prevalence of cardiovascularmalformations was 1.5% for paroxetine vs. 1% for other antidepressants. This study alsosuggested an increased risk of overall major congenital malformations (inclusive of thecardiovascular defects) for paroxetine compared to other antidepressants (OR 1.8; 95%confidence interval 1.2-2.8). The prevalence of all congenital malformations was 4% forparoxetine vs. 2% for other antidepressants. It is important to note that because this studywas designed to evaluate the relative risk of congenital malformations in infants born towomen exposed to antidepressants, the study did not include a comparison to infants whowere not exposed to any antidepressant. Therefore, these data should also be viewedwithin the context of the overall prevalence of congenital malformations in the generalpopulation, which is estimated in the U.S. to be approximately 3% for any malformationand approximately 1% for cardiovascular malformations alone (Honein 1999).
A new study of delivery outcome following maternal use of SSRI antidepressants in earlypregnancy has been conducted utilizing the Swedish national registry data. Previouspublished studies utilizing these registry data, and cited in the previous version of theparoxetine Prescribing Information, found no evidence for an increased overall risk ofmajor malformations with maternal exposure to SSRI medications, including paroxetine(Hallberg 2005, Ericson 1999). In this latest study, the population that was investigatedcomprised infants of 6,896 women exposed to antidepressants in early pregnancy(including 5,175 infants born to 5,123 women reporting the use of any SSRI in the firsttrimester). Among them, 815 women reported the use of paroxetine and they delivered822 infants. Rates of malformations in these infants were compared with the generalpopulation experience. No increase in the overall rate of congenital malformations wasobserved in infants exposed to paroxetine (4.9%), compared with the general populationrate (4.8%) (adjusted OR: 1.03; 95% confidence interval 0.75-1.41). There was,however, an increased risk for cardiac defects in infants exposed to paroxetine (OR 1.78,95% confidence interval 1.12-2.75), which was contributed mainly by an increased riskof VSD and ASD (OR 1.92; 95% confidence interval 1.12-3.10); 13 of 19 paroxetine-exposed infants with cardiac defects had a VSD or ASD. An increased risk of cardiacdefects was not observed in infants whose mothers received an SSRI other thanparoxetine (OR 0.92; 95% confidence interval 0.89-1.21). The rate of cardiacmalformations in infants exposed to paroxetine was approximately 2% for paroxetine vs1% in the general population.
In addition to the above, an abstract presented at the 33rd Annual Conference of theEuropean Teratology Society (3rd-7th September 2005) reported a smaller studyexamining pregnancy outcomes in pregnant women exposed to paroxetine or fluoxetinewho contacted two teratogen information services in Israel and Italy (Diav-Citrin 2005).
There was a higher overall rate of major congenital malformations in infants exposed to paroxetine in the first trimester (13/257 [5.1%]) compared to infants in a control groupwith drug exposures not known to be teratogenic (28/1062 [2.6%]) (relative risk [RR]1.92; 95% confidence interval 1.01-3.65). A higher rate of cardiovascular anomalies wasalso observed in the paroxetine group (5/257 [1.9%]) compared to the control group(6/1066 [0.6%]) (RR 3.46; 95% confidence interval 1.06-11.2). Similar trends werereported in the fluoxetine group, but did not reach statistical significance PAXIL is indicated for the treatment of major depressive disorder, obsessive-compulsivedisorder, panic disorder, social anxiety disorder, generalized anxiety disorder, andposttraumatic stress disorder; PAXIL CR is indicated for the treatment of majordepressive disorder, panic disorder, social anxiety disorder, and premenstrual dysphoricdisorder.
The medical community can further our understanding of PAXIL and PAXIL CR byreporting adverse events to GlaxoSmithKline at 1-888-825-5249 or to the FDAMEDWATCH program by phone at 1-800-FDA-1088, by FAX at 1-800-FDA-0178, bymodem at 1-800-FDA-7737 or by mail: MEDWATCH HF-2FDA5600 Fisher’s LaneRockville, 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 CustomerResponse Center at 1-888-825-5249.
Jack Modell, MDVice PresidentClinical Psychiatry – North AmericaGlaxoSmithKline

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