Approved Drug Label (PDF)
5
Warnings and Precautions
5.2 Serotonin Syndrome
Additions
and revisions underlined:
Serotonin-norepinephrine reuptake inhibitors (SNRIs) and
SSRIs, including PAXIL CR, can
precipitate serotonin syndrome, a potentially
life-threatening condition. The risk is increased
with concomitant use of other serotonergic drugs (including triptans,
tricyclic antidepressants,
fentanyl, lithium, tramadol, meperidine, methadone, tryptophan,
buspirone, amphetamines, and
St. John's Wort) and with drugs that impair metabolism of
serotonin, i.e., MAOIs [see
Contraindications (4), Drug Interactions (7.1)].
5.4 Embryofetal Toxicity
Additions
and revisions underlined:
Based on meta-analyses of epidemiological studies, exposure
to paroxetine in the first trimester
of pregnancy is associated with a less than 2-fold
increase in the rate of cardiovascular
malformations among infants. For women who intend to
become pregnant or who are in their
first trimester of pregnancy, PAXIL CR, should be initiated
only after consideration of the other
available treatment options [see Use in Specific
Populations (8.1)].
5.5 Increased Risk of Bleeding
Newly
added information:
Based on data from the published observational studies,
exposure to SSRIs,
particularly in the month before delivery, has been
associated with a less than 2-fold increase in
the risk of postpartum hemorrhage [see Use in
Specific Populations (8.1)].
6
Adverse Reactions
6.2 Postmarketing Experience
Additions
and revisions underlined:
Because these reactions are reported voluntarily from a
population of unknown size, it is not always
possible to reliably estimate their frequency or establish a
causal relationship to drug exposure.
Acute pancreatitis, elevated liver function tests (the most severe
cases were deaths due to liver
necrosis, and grossly elevated transaminases associated with
severe liver dysfunction),
Guillain-Barré syndrome, Stevens-Johnson syndrome, toxic
epidermal necrolysis, drug reaction
with eosinophilia and systemic symptoms (DRESS), priapism,
syndrome of inappropriate ADH
secretion (SIADH), prolactinemia and galactorrhea;
extrapyramidal symptoms which have
included akathisia, bradykinesia, cogwheel rigidity,
dystonia, hypertonia, trismus; status
epilepticus, acute renal failure, pulmonary hypertension,
allergic alveolitis, anosmia, hyposmia,
anaphylaxis, eclampsia, laryngismus, optic neuritis,
porphyria, restless legs syndrome (RLS),
ventricular fibrillation, ventricular tachycardia (including
torsade de pointes), hemolytic anemia,
events related to impaired hematopoiesis (including aplastic
anemia, pancytopenia, bone marrow
aplasia, and agranulocytosis), and vasculitic syndromes
(such as Henoch-Schönlein purpura).
7
Drug Interactions
7.1 Clinically Significant Drug Interactions
Addition of opioids and amphetamines to
table
8
Use in Specific Populations
8.1 Pregnancy
Additions
and revisions underlined:
Pregnancy Exposure
Registry
There
is a pregnancy exposure registry that monitors pregnancy outcomes in women
exposed to
antidepressants
during pregnancy. Healthcare providers are encouraged to register patients by
calling
the National Pregnancy Registry for Antidepressants at 1-866-961-2388 or
visiting online
at https://womensmentalhealth.org/clinical-and-researchprograms/
pregnancyregistry/antidepressants/.
Risk
Summary
Based
on data from published observational studies, exposure to SSRIs, particularly
in the month
before
delivery, has been associated with a less than 2-fold increase in the risk of
postpartum
hemorrhage [see Warnings and Precautions (5.5)
and Clinical Considerations].
PAXIL
CR is associated with a less than 2-fold increase in cardiovascular
malformations when
administered
to a pregnant woman during the first trimester. While individual
epidemiological
studies
on the association between paroxetine use and cardiovascular malformations have
reported
inconsistent findings, some meta-analyses of epidemiological studies have
identified an
increased
risk of cardiovascular malformations (see Data). There are risks of
persistent
pulmonary
hypertension of the newborn (PPHN) (see Data) and/or poor neonatal
adaptation with
exposure
to selective serotonin reuptake inhibitors (SSRIs), including PAXIL CR, during
pregnancy.
There also are risks associated with untreated depression in pregnancy (see
Clinical
Considerations). For
women who intend to become pregnant or who are in their first trimester of
pregnancy, paroxetine should be
initiated only after
consideration of the other available
treatment options.
No
evidence of treatment related malformations was observed in animal reproduction
studies,
when
paroxetine was administered during the period of organogenesis at doses up to
50
mg/kg/day
in rats and 6 mg/kg/day in rabbits. These doses are approximately 6 (rat) and
less than
2
(rabbit) times the maximum recommended human dose (MRHD – 75 mg) on an mg/m2 basis.
When
paroxetine was administered to female rats during the last trimester of
gestation and
continued
through lactation, there was an increase in the number of pup deaths during the
first
four
days of lactation. This effect occurred at a dose of 1 mg/kg/day which is less
than the
MRHD
on an mg/m2 basis (see Data).
The
estimated background risks of major birth defects and miscarriage for the
indicated
populations
are unknown. All pregnancies have a background risk of birth defect, loss, or
other
adverse
outcomes. In the US general population, the estimated background risk of major
birth
defects
and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to
20%,
respectively.
Clinical
Considerations
Disease-associated
maternal and/or embryo/fetal risk
Women
who discontinue antidepressants during pregnancy are more likely to experience
a
relapse
of major depression than women who continue antidepressants. This finding is
from a
prospective
longitudinal study of 201 pregnant women with a history of major depressive
disorder
who were euthymic and taking antidepressants at the beginning of pregnancy.
Consider
the
risks of untreated depression when discontinuing or changing treatment with
antidepressant
medication
during pregnancy and postpartum.
Maternal
Adverse Reactions
Use of
PAXIL CR in the month before delivery may be associated with an increased risk
of
postpartum
hemorrhage [see Warnings and Precautions (5.5)].
Fetal/Neonatal
adverse reactions
Neonates exposed to PAXIL
CR and other SSRIs late in the third trimester have developed
complications requiring prolonged
hospitalization, respiratory support, and tube feeding. Such
complications can arise immediately
upon delivery. Reported clinical findings have included
respiratory distress, cyanosis,
apnea, seizures, temperature instability, feeding difficulty,
vomiting,
hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremors, jitteriness,
irritability,
and constant crying. These findings
are consistent with either a direct toxic effect of SSRIs or
possibly
a drug discontinuation syndrome. It should be noted that, in some cases, the clinical
picture
is consistent with serotonin syndrome [see Warnings and Precautions (5.4)].
Data
Human
Data
Published
epidemiological studies on the association between first trimester paroxetine
use and
cardiovascular
malformations have reported inconsistent results; however, meta-analyses of
population-based
cohort studies published between 1996-2017 indicate a less than 2-fold
increased
risk for overall cardiovascular malformations. Specific cardiac malformations
identified
in two meta-analyses include approximately 2 to 2.5-fold increased risk for
right
ventricular
outflow tract defects. One meta-analysis also identified an increased risk
(less than 2-
fold)
for bulbus cordis anomalies and anomalies of cardiac septal closure, and an
increased risk
for
atrial septal defects (pooled OR 2.38, 95% CI 1.14-4.97). Important limitations
of the studies
included
in these meta-analyses include potential confounding by indication, depression
severity,
and
potential exposure misclassification.
Exposure to SSRIs, particularly
later
in pregnancy,
may have an increased risk for PPHN. PPHN
occurs in 1-2 per 1000 live births in the general
population and is associated with substantial
neonatal morbidity and mortality.
. . .
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Medication Guide
Additions
and revisions underlined:
o Taking PAXIL CR during your first trimester of
pregnancy may cause your baby to be at an increased risk of
having a heart problem (cardiac malformations) at birth.
o Taking PAXIL CR during your third trimester of
pregnancy may cause your baby to have breathing,
temperature, and feeding problems, low muscle tone
(floppy baby syndrome), and irritability after birth and
may
cause your baby to be at an increased risk of a serious lung problem at birth.
o There is a pregnancy registry for females who are
exposed to PAXIL CR during pregnancy. The purpose of
the registry is to collect information about the health
of females exposed to PAXIL CR and their baby. If
you become pregnant during treatment with PAXIL CR talk
to your healthcare provider about registering
with the National Pregnancy Registry for Antidepressants
at 1-866-961-2388 or visit online at
https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants/.
Especially tell your healthcare provider if you take:
• medicines used to treat migraine headaches called triptans
• tricyclic antidepressants
• lithium
• tramadol, fentanyl, meperidine, methadone, or other
opioids
PATIENT COUNSELING INFORMATION
Additions
and revisions underlined:
Caution patients about the risk of serotonin
syndrome, particularly with the concomitant use of
PAXIL CR with other serotonergic drugs
including triptans, tricyclic antidepressants, opioids,
lithium, tryptophan, buspirone, amphetamines, St. John’s Wort, and with drugs that impair
metabolism of serotonin (in
particular, MAOIs, both those intended to treat psychiatric disorders
and also others, such as linezolid).
Advise
women to notify their healthcare provider if they become pregnant or intend to
become
pregnant
during treatment with PAXIL CR. Advise women of risks associated with first
trimester
use of
PAXIL CR and that use later in pregnancy may lead to an increased risk for
neonatal
complications
requiring prolonged hospitalization, respiratory support, tube feeding, and/or
Reference
ID: 5229507
persistent
pulmonary hypertension of the newborn (PPHN) [see Warnings and Precautions (5.4),
Use in
Specific Populations (8.1)].
Advise women that there is a pregnancy exposure registry
that
monitors pregnancy outcomes in women exposed to PAXIL CR during pregnancy [see
Warnings
and Precautions (5.4), Use
in Specific Populations (8.1)].
Lactation
Advise
breastfeeding women using PAXIL CR to monitor infants for agitation,
irritability, poor
feeding
and poor weight gain and to seek medical care if they notice these signs [see
Use in
Specific
Populations (8.2)].
Females
and Males of Reproductive Potential
Advise
men that PAXIL CR may affect sperm quality, which may impair fertility; it is
unknown
if
this effect is reversible [see Use in Specific Populations (8.3)]
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