Drug Reaction with Eosinophilia and Systemic
Symptoms (DRESS)
(Newly
added subsection)
Drug Reaction
with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients
taking NSAIDs such as indomethacin capsules. Some of these events
have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling.
Other clinical
manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis.
Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder
is variable in its presentation, other organ systems not noted here may
be involved. It is important
to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present
even though rash is not evident. If such signs or symptoms are present, discontinue indomethacin capsules and evaluate the patient
immediately.
Fetal Toxicity
(Newly
added subsection)
Premature Closure of Fetal Ductus Arteriosus
Avoid use of NSAIDs,
including indomethacin capsules, in pregnant
women at about
30 weeks gestation and later. NSAIDs including indomethacin capsules, increase the risk of premature
closure of the fetal ductus arteriosus at approximately this gestational age.
Oligohydramnios/Neonatal Renal Impairment
Use of NSAIDs, including indomethacin capsules, 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 indomethacin capsules
use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic
fluid if indomethacin capsules treatment extends beyond 48 hours.
Discontinue indomethacin capsules
if oligohydramnios occurs and follow up according
to clinical practice
[see PRECAUTIONS; Pregnancy].
(Additions and/or revisions underlined)
Risk Summary
Use of NSAIDs,
including indomethacin capsules, 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 indomethacin capsules use between about 20 and 30 weeks of gestation, and avoid indomethacin capsules use at about 30 weeks of gestation and later in pregnancy [see WARNINGS; Fetal Toxicity].
Premature Closure of Fetal Ductus Arteriosus
Use of NSAIDs, including indomethacin capsules, 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 indomethacin capsules, can cause premature closure of the fetal ductus arteriosus (see WARNINGS; Fetal Toxicity).
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 indomethacin capsules treatment extends beyond 48 hours,
consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue indomethacin capsules and follow
up according to clinical practice (see WARNINGS;
Fetal Toxicity).
Labor and Delivery
There are no studies on the effects of indomethacin capsules during
labor and delivery. In animal
studies, NSAIDs,
including indomethacin, inhibit prostaglandin synthesis, caused delayed parturition, and increase the incidence
of stillbirths.
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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