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Premature Closure of Fetal
Ductus Arteriosus
Avoid use of NSAIDs,
including INDOCIN SR, in pregnant
women at about 30 weeks of
gestation and later.
NSAIDs, including INDOCIN SR,
increase the risk of premature
closure of the fetal ductus arteriosus
at approximately this
gestational age.
Oligohydramnios/Neonatal Renal
Impairment
Use of NSAIDs, including INDOCIN SR, at about 20 weeks
gestation or later in pregnancy
may cause fetal renal dysfunction leading
to oligohydramnios and, in some cases,
neonatal renal impairment. These adverse outcomes are seen, on average,
after days to weeks of treatment, although oligohydramnios has
been infrequently reported as soon as 48 hours after NSAID
initiation.
Oligohydramnios is often, but not always, reversible with treatment
discontinuation. Complications
of prolonged oligohydramnios may,
for example, include limb contractures and delayed lung maturation. In some postmarketing cases of
impaired neonatal renal function,
invasive procedures such as exchange
transfusion or dialysis were required.
If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation,
limit INDOCIN SR use to the lowest effective dose and
shortest duration possssible. Consider
ultrasound monitoring of amniotic
fluid if INDOCIN SR treatment extends beyond 48 hours. Discontinue
INDOCIN SR if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations
(8.1)].
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Risk Summary
Use of
NSAIDs, including
INDOCIN SR, can cause premature closure of the fetal ductus
arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal
renal impairment. Because
of these risks,
limit dose and duration
of INDOCIN SR use between about 20 and 30 weeks
of gestation, and avoid INDOCIN
SR use at about 30
weeks of gestation and later in pregnancy (see Clinical Considerations, Data).
Premature
Closure of Fetal Ductus Arteriosus
Use of NSAIDS, including INDOCIN SR, at about 30 weeks
gestation or later in pregnancy
increases the risk of premature
closure of the fetal ductus arteriosus.
Oligohydramnios/Neonatal Renal Impairment
Use of NSAIDs at
about 20 weeks gestation or later in pregnancy has been associated with cases of
fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment.
Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first
or second trimesters of pregnancy
are inconclusive. In animal reproduction studies
retarded fetal ossification was observed with administration
of
indomethacin to mice and
rats during organogenesis at doses 0.1 and 0.2 times, respectively, the maximum recommended human dose (MRHD, 200 mg).
In published studies in pregnant
mice, indomethacin produced
maternal toxicity and death, increased fetal resorptions, and fetal
malformations at 0.1 times
the MRHD. When rat and mice
dams were dosed during the last
three days of gestation, indomethacin produced
neuronal necrosis in the offspring at 0.1 and 0.05 times the MRHD, respectively
[see Data]. Based
on animal
data, prostaglandins have
been shown to have an important role in endometrial vascular permeability,
blastocyst implantation, and decidualization. In animal studies,
administration of prostaglandin synthesis
inhibitors such as indomethacin,
resulted in increased pre- and post-implantation loss. Prostaglandins also have
been shown to have an important role in fetal kidney development.
In published animal studies, prostaglandin synthesis inhibitors
have been reported to impair
kidney development when administered at clinically relevant
doses.
The estimated background risk of major birth defects and miscarriage for the indicated
population(s) is unknown. All
pregnancies have a background
risk of birth defect, loss,
or other adverse outcomes. In the U.S.
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
Fetal/Neonatal
Adverse Reactions
Premature Closure
of Fetal Ductus
Arteriosus:
Avoid use of NSAIDs in
women at about 30 weeks gestation
and later in pregnancy, because NSAIDs, including INDOCIN SR, can cause premature closure of the fetal ductus arteriosus (see Data).
Oligohydramnios/Neonatal Renal Impairment:
If an NSAID is necessary
at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration
possible. If INDOCIN
SR treatment extends
beyond 48 hours, consider
monitoring with ultrasound
for oligohydramnios. If oligohydramnios occurs, discontinue INDOCIN SR and follow up according to clinical practice (see Data).
Human Data
Premature Closure
of Fetal Ductus
Arteriosus:
Published literature reports that the use of NSAIDs
at about 30 weeks of
gestation and later in pregnancy may cause premature closure of the fetal ductus
arteriosus.
Oligohydramnios/Neonatal Renal Impairment:
Published
studies and postmarketing reports describe maternal NSAID use
at
about 20 weeks gestation
or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal
renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after
NSAID initiation. In many cases,
but not all, the decrease
in amniotic fluid was transient
and reversible with cessation
of the drug.
There have been a limited
number of case reports
of maternal NSAID use and neonatal
renal dysfunction without oligohydramnios, some of
which were irreversible. Some cases of neonatal renal dysfunction required treatment
with invasive procedures, such as exchange transfusion or dialysis.
Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant
use of other medications. These limitations preclude establishing a reliable
estimate of the risk of adverse
fetal and neonatal
outcomes with maternal
NSAID use. Because
the published safety
data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term
infant exposed to NSAIDs through maternal use is uncertain.
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Serious Skin Reactions, including
DRESS
Advise patients to stop taking
INDOCIN SR immediately if they
develop any type of rash or fever and to
contact their healthcare provider as soon as possible [see Warnings and Precautions
(5.9, 5.10)].
Female Fertility
Advise females of reproductive potential who desire pregnancy
that NSAIDs, including INDOCIN SR,
may be associated with a reversible
delay in ovulation [see Use in Specific
Populations (8.3)].
Fetal Toxicity
Inform pregnant women to avoid use
of INDOCIN SR and other NSAIDs
starting at 30 weeks gestation
because of the risk of the premature closing of the fetal ductus
arteriosus. If treatment with INDOCIN
SR is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for
oligohydramnios, if
treatment continues for longer
than 48 hours [see Warnings and Precautions (5.11) and Use in Specific Populations (8.1)].
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