Approved Drug Label (PDF)
5
Warnings and Precautions
5.10 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 INDOCIN.
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 INDOCIN and evaluate
the patient immediately.
5.11 Fetal Toxicity
(Subsection title revised; Additions and/or revisions underlined)
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)].
8
Use in Specific Populations
8.1 Pregnancy
(Additions and/or
revisions underlined)
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). 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.
…
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
(Additions and/or
revisions underlined)
…
Before taking
NSAIDs, tell your healthcare provider about all of your medical conditions,
including if you:
have
liver or kidney problems
have
high blood pressure
have
asthma
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.
- are
breastfeeding or plan to breast feed.
…
PATIENT COUNSELING INFORMATION
(Additions and/or
revisions underlined)
Advise
the patient to read the FDA-approved patient labeling (Medication Guide) that
accompanies each prescription dispensed. Inform patients, families, or their caregivers
of the following information before initiating therapy with INDOCIN and
periodically during the course of ongoing therapy.
Cardiovascular
Thrombotic Events
Advise
patients to be alert for the symptoms of cardiovascular thrombotic events, including
chest pain, shortness of breath, weakness, or slurring of speech, and to report
any of these symptoms to their health care provider immediately [see Warnings and Precautions (5.1)].
Gastrointestinal
Bleeding, Ulceration, and Perforation
Advise
patients to report symptoms of ulcerations and bleeding, including epigastric
pain, dyspepsia, melena, and hematemesis to their health care provider. In the
setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients
of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions (5.2)].
Hepatotoxicity
Inform
patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue,
lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and
“flu-like” symptoms). If these occur, instruct patients to stop INDOCIN and seek
immediate medical therapy [see Warnings
and Precautions (5.3)].
Heart
Failure and Edema
Advise
patients to be alert for the symptoms of congestive heart failure including shortness
of breath, unexplained weight gain, or edema and to contact their healthcare
provider if such symptoms occur [see
Warnings and Precautions (5.5)].
Anaphylactic
Reactions
Inform
patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling
of the face or throat). Instruct patients to seek immediate emergency help if
these occur [see Contraindications (4)
and Warnings and Precautions (5.7)].
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)].
Avoid
Concomitant Use of NSAIDs
Inform
patients that the concomitant use of INDOCIN with other NSAIDs or salicylates (e.g.,
diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal
toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2) and Drug Interactions (7)]. Alert
patients that NSAIDs may be present in “over the counter” medications for
treatment of colds, fever, or insomnia.
Use
of NSAIDs and Low-Dose Aspirin
Inform
patients not to use low-dose aspirin concomitantly with INDOCIN until they talk
to their healthcare provider [see Drug
Interactions (7)].