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Premature Closure of Fetal
Ductus Arteriosus
Avoid use of NSAIDS,
including INDOCIN, in pregnant women at
about 30 weeks of gestation and later. NSAIDs, including
INDOCIN, 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, 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 use to the lowest effective dose and shortest duration possssible. Consider ultrasound monitoring of amniotic
fluid if INDOCIN treatment extends beyond 48 hours. Discontinue INDOCIN 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, 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 use between
about 20 and 30 weeks of
gestation, and avoid INDOCIN
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, 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
(40 mL)).
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, 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
treatment extends
beyond 48 hours, consider
monitoring with ultrasound
for oligohydramnios. If oligohydramnios occurs, discontinue INDOCIN and follow up according to clinical practice
(see Data).
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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Before taking NSAIDs, tell your healthcare provider about
all of your medical conditions, including if you:
• are pregnant or plan to become pregnant.Taking NSAIDs
at about 20 weeks of pregnancy or later may
harm your unborn baby. If you need to NSAIDs for more
than 2 days when you are between 20 and 30
weeks of pregnancy, your healthcare provider may
need to monitor the amount of fluid in your womb
around your baby. You should not take NSAIDs after about
30 weeks of pregnancy.
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Serious Skin Reactions, including
DRESS
Advise patients to stop taking INDOCIN 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,
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 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
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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