WARNINGS
Included as part of the PRECAUTIONS section.
PRECAUTIONS
Cardiovascular Thrombotic Events
Clinical trials of several COX-2 selective and
nonselective NSAIDs of up to three years duration have shown an increased risk
of serious cardiovascular (CV) thrombotic events, including myocardial infarction
(MI) and stroke, which can be fatal. Based on available data, it is unclear
that the risk for CV thrombotic events is similar for all NSAIDs. The relative
increase in serious CV thrombotic events over baseline conferred by NSAID use appears
to be similar in those with and without known CV disease or risk factors for CV
disease. However, patients with known CV disease or risk factors had a higher
absolute incidence of excess serious CV thrombotic events, due to their
increased baseline rate. Some observational studies found that this increased
risk of serious CV thrombotic events began as early as the first weeks of
treatment. The increase in CV thrombotic risk has been observed most consistently
at higher doses.
To minimize the potential risk for an adverse CV event in
NSAID-treated patients, use the lowest effective dose for the shortest duration
possible. Physicians and patients should remain alert for the development of
such events, throughout the entire treatment course, even in the absence of
previous CV symptoms. Patients should be informed about the symptoms of serious
CV events and the steps to take if they occur.
There is no consistent evidence that concurrent use of
aspirin mitigates the increased risk of serious CV thrombotic events associated
with NSAID use. The concurrent use of aspirin and an NSAID, such as
indomethacin, increases the risk of serious gastrointestinal (GI) events [see Gastrointestinal Bleeding, Ulceration, And Perforation].
Status Post Coronary Artery Bypass Graft (CABG) Surgery
Two large, controlled clinical trials of a COX-2
selective NSAID for the treatment of pain in the first 10–14 days following
CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs
are contraindicated in the setting of CABG [see CONTRAINDICATIONS].
Post-MI Patients
Observational studies conducted in the Danish National
Registry have demonstrated that patients treated with NSAIDs in the post-MI
period were at increased risk of reinfarction, CV-related death, and allcause mortality
beginning in the first week of treatment. In this same cohort, the incidence of
death in the first year post-MI was 20 per 100 person years in NSAID-treated
patients compared to 12 per 100 person years in non-NSAID exposed patients.
Although the absolute rate of death declined somewhat after the first year
post-MI, the increased relative risk of death in NSAID users persisted over at
least the next four years of follow-up.
Avoid the use of INDOCIN in patients with a recent MI
unless the benefits are expected to outweigh the risk of recurrent CV
thrombotic events. If INDOCIN is used in patients with a recent MI, monitor patients
for signs of cardiac ischemia.
Gastrointestinal Bleeding, Ulceration, And Perforation
NSAIDs, including indomethacin, cause serious
gastrointestinal (GI) adverse events including inflammation, bleeding,
ulceration, and perforation of the esophagus, stomach, small intestine, or
large intestine, which can be fatal. These serious adverse events can occur at
any time, with or without warning symptoms, in patients treated with NSAIDs.
Only one in five patients who develop a serious upper GI adverse event on NSAID
therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused
by NSAIDs occurred in approximately 1% of patients treated for 3-6 months, and
in about 2%-4% of patients treated for one year. However, even short-term NSAID
therapy is not without risk.
Risk Factors For GI Bleeding, Ulceration, And Perforation
Patients with a prior history of peptic ulcer disease
and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk
for developing a GI bleed compared to patients without these risk factors. Other
factors that increase the risk of GI bleeding in patients treated with NSAIDs
include longer duration of NSAID therapy; concomitant use of oral
corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake
inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health
status. Most postmarketing reports of fatal GI events occurred in elderly or
debilitated patients. Additionally, patients with advanced liver disease and/or
coagulopathy are at increased risk for GI bleeding.
Strategies to Minimize the GI Risks in NSAID-treated
patients:
- Use the lowest effective dosage for the shortest possible
duration.
- Avoid administration of more than one NSAID at a time.
- Avoid use in patients at higher risk unless benefits are
expected to outweigh the increased risk of bleeding. For such patients, as well
as those with active GI bleeding, consider alternate therapies other than
NSAIDs.
- Remain alert for signs and symptoms of GI ulceration and
bleeding during NSAID therapy.
- If a serious GI adverse event is suspected, promptly
initiate evaluation and treatment, and discontinue INDOCIN until a serious GI
adverse event is ruled out.
- In the setting of concomitant use of low-dose aspirin for
cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding
[see DRUG INTERACTIONS].
Hepatotoxicity
Elevations of ALT or AST (three or more times the upper
limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated
patients in clinical trials. In addition, rare, sometimes fatal, cases of
severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic
failure have been reported.
Elevations of ALT or AST (less than three times ULN) may
occur in up to 15% of patients treated with NSAIDs including indomethacin.
Inform patients of the warning signs and symptoms of
hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice,
right upper quadrant tenderness, and “flu-like” symptoms). If
clinical signs and symptoms consistent with liver disease develop, or if
systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue
INDOCIN immediately, and perform a clinical evaluation of the patient.
Hypertension
NSAIDs, including INDOCIN, can lead to new onset of
hypertension or worsening of preexisting hypertension, either of which may
contribute to the increased incidence of CV events. Patients taking angiotensin
converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may
have impaired response to these therapies when taking NSAIDs [see DRUG INTERACTIONS].
Monitor blood pressure (BP) during the initiation of NSAID
treatment and throughout the course of therapy.
Heart Failure And Edema
The Coxib and traditional NSAID Trialists' Collaboration
meta-analysis of randomized controlled trials demonstrated an approximately
two-fold increase in hospitalizations for heart failure in COX-2 selective-treated
patients and nonselective NSAID-treated patients compared to placebo-treated patients.
In a Danish National Registry study of patients with heart failure, NSAID use
increased the risk of MI, hospitalization for heart failure, and death.
Additionally, fluid retention and edema have been
observed in some patients treated with NSAIDs. Use of indomethacin may blunt
the CV effects of several therapeutic agents used to treat these medical conditions
(e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see DRUG INTERACTIONS].
Avoid the use of INDOCIN in patients with severe heart
failure unless the benefits are expected to outweigh the risk of worsening
heart failure. If INDOCIN is used in patients with severe heart failure, monitor
patients for signs of worsening heart failure.
Renal Toxicity And Hyperkalemia
Renal Toxicity
Long-term administration of NSAIDs has resulted in renal
papillary necrosis and other renal injury.
Renal toxicity has also been seen in patients in whom
renal prostaglandins have a compensatory role in the maintenance of renal
perfusion. In these patients, administration of an NSAID may cause a
dosedependent reduction in prostaglandin formation and, secondarily, in renal
blood flow, which may precipitate overt renal decompensation. Patients at
greatest risk of this reaction are those with impaired renal function,
dehydration, hypovolemia, heart failure, liver dysfunction, those taking
diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID
therapy is usually followed by recovery to the pretreatment state.
No information is available from controlled clinical
studies regarding the use of INDOCIN in patients with advanced renal disease.
The renal effects of INDOCIN may hasten the progression of renal dysfunction in
patients with preexisting renal disease.
Correct volume status in dehydrated or hypovolemic
patients prior to initiating INDOCIN. Monitor renal function in patients with
renal or hepatic impairment, heart failure, dehydration, or hypovolemia during
use of INDOCIN [see DRUG INTERACTIONS]. Avoid the use of INDOCIN in
patients with advanced renal disease unless the benefits are expected to
outweigh the risk of worsening renal function. If INDOCIN is used in patients
with advanced renal disease, monitor patients for signs of worsening renal
function.
It has been reported that the addition of the
potassium-sparing diuretic, triamterene, to a maintenance schedule of
indomethacin resulted in reversible acute renal failure in two of four healthy
volunteers. Indomethacin and triamterene should not be administered together.
Hyperkalemia
Increases in serum potassium concentration, including
hyperkalemia, have been reported with use of NSAIDs, even in some patients
without renal impairment. In patients with normal renal function, these effects
have been attributed to a hyporeninemic-hypoaldosteronism state.
Both Indomethacin and potassium-sparing diuretics may be
associated with increased serum potassium levels. The potential effects of
indomethacin and potassium-sparing diuretics on potassium levels and renal
function should be considered when these agents are administered concurrently.
Anaphylactic Reactions
Indomethacin has been associated with anaphylactic
reactions in patients with and without known hypersensitivity to indomethacin
and in patients with aspirin-sensitive asthma [see CONTRAINDICATIONS and
Exacerbation Of Asthma Related To Aspirin Sensitivity].
Seek emergency help if an anaphylactic reaction occurs.
Exacerbation Of Asthma Related To Aspirin Sensitivity
A subpopulation of patients with asthma may have
aspirin-sensitive asthma which may include chronic rhinosinusitis complicated
by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin
and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has
been reported in such aspirin-sensitive patients, INDOCIN is contraindicated in
patients with this form of aspirin sensitivity [see CONTRAINDICATIONS].
When INDOCIN is used in patients with preexisting asthma (without known aspirin
sensitivity), monitor patients for changes in the signs and symptoms of asthma.
Serious Skin Reactions
NSAIDs, including indomethacin, can cause serious skin
adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome
(SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious
events may occur without warning. Inform patients about the signs and symptoms
of serious skin reactions, and to discontinue the use of INDOCIN at the first
appearance of skin rash or any other sign of hypersensitivity. INDOCIN is
contraindicated in patients with previous serious skin reactions to NSAIDs [see CONTRAINDICATIONS].
Premature Closure Of Fetal Ductus Arteriosus
Indomethacin may cause premature closure of the fetal
ductus arteriosus. Avoid use of NSAIDs, including INDOCIN, in pregnant women
starting at 30 weeks of gestation (third trimester) [see Use In Specific Populations].
Hematologic Toxicity
Anemia has occurred in NSAID-treated patients. This may
be due to occult or gross blood loss, fluid retention, or an incompletely
described effect on erythropoiesis. If a patient treated with INDOCIN has any
signs or symptoms of anemia, monitor hemoglobin or hematocrit.
NSAIDs, including INDOCIN, may increase the risk of
bleeding events. Co-morbid conditions, such as coagulation disorders, or
concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin),
serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake
inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of
bleeding [see DRUG INTERACTIONS].
Masking Of Inflammation And Fever
The pharmacological activity of INDOCIN in reducing
inflammation, and possibly fever, may diminish the utility of diagnostic signs
in detecting infections.
Laboratory Monitoring
Because serious GI bleeding, hepatotoxicity, and renal
injury can occur without warning symptoms or signs, consider monitoring
patients on long-term NSAID treatment with a CBC and a chemistry profile periodically
[see Gastrointestinal Bleeding, Ulceration, And Perforation, Hepatotoxicity and Renal Toxicity and Hyperkalemia].
Central Nervous System Effects
INDOCIN may aggravate depression or other psychiatric
disturbances, epilepsy, and parkinsonism, and should be used with considerable
caution in patients with these conditions. Discontinue INDOCIN if severe CNS
adverse reactions develop.
INDOCIN may cause drowsiness; therefore, caution patients
about engaging in activities requiring mental alertness and motor coordination,
such as driving a car. Indomethacin may also cause headache. Headache which
persists despite dosage reduction requires cessation of therapy with INDOCIN.
Ocular Effects
Corneal deposits and retinal disturbances, including
those of the macula, have been observed in some patients who had received
prolonged therapy with INDOCIN. Be alert to the possible association between
the changes noted and INDOCIN. It is advisable to discontinue therapy if such
changes are observed. Blurred vision may be a significant symptom and warrants
a thorough ophthalmological examination. Since these changes may be
asymptomatic, ophthalmologic examination at periodic intervals is desirable in
patients receiving prolonged therapy. INDOCIN is not indicated for long-term treatment.
Patient Counseling Information
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].
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].
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].
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].
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 and
WARNINGS AND PRECAUTIONS].
Serious Skin Reactions
Advise patients to stop INDOCIN immediately if they
develop any type of rash and to contact their healthcare provider as soon as
possible [see WARNINGS AND PRECAUTIONS].
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].
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 [see WARNINGS AND PRECAUTIONS and
Use In Specific Populations].
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 and DRUG INTERACTIONS].
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].
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Carcinogenesis
In an 81-week chronic oral toxicity study in the rat at
doses up to 1 mg/kg/day (0.05 times the MRHD on a mg/m² basis), indomethacin
had no tumorigenic effect. Indomethacin produced no neoplastic or hyperplastic
changes related to treatment in carcinogenic studies in the rat (dosing period
73 to 110 weeks) and the mouse (dosing period 62 to 88 weeks) at doses up to
1.5 mg/kg/day (0.04 times [mice] and 0.07 times [rats] the MRHD on a mg/m²
basis, respectively).
Mutagenesis
Indomethacin did not have any mutagenic effect in in
vitro bacterial tests and a series of in vivo tests including the host-mediated
assay, sex-linked recessive lethals in Drosophila, and the micronucleus test in
mice.
Impairment Of Fertility
Indomethacin at dosage levels up to 0.5 mg/kg/day had no
effect on fertility in mice in a two generation reproduction study (0.01 times
the MRHD on a mg/m² basis) or a two litter reproduction study in rats (0.02
times the MRHD on a mg/m² basis).
Use In Specific Populations
Pregnancy
Risk Summary
Use of NSAIDs, including INDOCIN, during the third
trimester of pregnancy increases the risk of premature closure of the fetal
ductus arteriosus. Avoid use of NSAIDs, including INDOCIN, in pregnant women
starting at 30 weeks of gestation (third trimester).
There are no adequate and well-controlled studies of
INDOCIN in pregnant women.
Data from observational studies regarding potential
embryofetal risks of NSAID use in women in the first or second trimesters of
pregnancy are inconclusive. In the general U.S. population, all clinically recognized
pregnancies, regardless of drug exposure, have a background rate of 2-4% for
major malformations, and 15-20% for pregnancy loss. 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.
Clinical Considerations
Labor or Delivery
There are no studies on the effects of INDOCIN during
labor or delivery. In animal studies, NSAIDs, including indomethacin, inhibit
prostaglandin synthesis, cause delayed parturition, and increase the incidence
of stillbirth.
Data
Animal data
Reproductive studies were conducted in mice and rats at
dosages of 0.5, 1.0, 2.0, and 4.0 mg/kg/day. Except for retarded fetal ossification
at 4 mg/kg/day (0.1 times [mice] and 0.2 times [rats] the MRHD on a mg/m²
basis, respectively) considered secondary to the decreased average fetal
weights, no increase in fetal malformations was observed as compared with
control groups. Other studies in mice reported in the literature using higher
doses (5 to 15 mg/kg/day, 0.1 to 0.4 times MRHD on a mg/m² basis) have described
maternal toxicity and death, increased fetal resorptions, and fetal
malformations.
In rats and mice, maternal indomethacin administration of
4.0 mg/kg/day (0.2 times and 0.1 times the MRHD on a mg/m² basis) during the
last 3 days of gestation was associated with an increased incidence of neuronal
necrosis in the diencephalon in the live-born fetuses however no increase in
neuronal necrosis was observed at 2.0 mg/kg/day as compared to the control
groups (0.1 times and 0.05 times the MRHD on a mg/m² basis). Administration of
0.5 or 4.0 mg/kg/day to offspring during the first 3 days of life did not cause
an increase in neuronal necrosis at either dose level.
Lactation
Risk Summary
Based on available published clinical data, indomethacin
may be present in human milk. The developmental and health benefits of
breastfeeding should be considered along with the mother's clinical need for INDOCIN
and any potential adverse effects on the breastfed infant from the INDOCIN or
from the underlying maternal condition.
Data
In one study, levels of indomethacin in breast milk were
below the sensitivity of the assay (<20 mcg/L) in 11 of 15 women using doses
ranging from 75 mg orally to 300 mg rectally daily (0.94 to 4.29 mg/kg daily)
in the postpartum period. Based on these levels, the average concentration
present in breast milk was estimated to be 0.27% of the maternal
weight-adjusted dose. In another study indomethacin levels were measured in
breast milk of eight postpartum women using doses of 75 mg daily and the
results were used to calculate an estimated infant daily dose. The estimated
infant dose of indomethacin from breast milk was less than 30 mcg/day or 4.5
mcg/kg/day assuming breast milk intake of 150 mL/kg/day. This is 0.5% of the
maternal weight-adjusted dosage or about 3% of the neonatal dose for treatment
of patent ductus arteriosus.
Females And Males Of Reproductive Potential
Infertility
Females
Based on the mechanism of action, the use of
prostaglandin-mediated NSAIDs, including INDOCIN, may delay or prevent rupture
of ovarian follicles, which has been associated with reversible infertility in
some women. Published animal studies have shown that administration of
prostaglandin synthesis inhibitors has the potential to disrupt
prostaglandin-mediated follicular rupture required for ovulation. Small studies
in women treated with NSAIDs have also shown a reversible delay in ovulation.
Consider withdrawal of NSAIDs, including INDOCIN, in women who have
difficulties conceiving or who are undergoing investigation of infertility.
Pediatric Use
Safety and effectiveness in pediatric patients 14 years
of age and younger has not been established.
INDOCIN should not be prescribed for pediatric patients
14 years of age and younger unless toxicity or lack of efficacy associated with
other drugs warrants the risk.
In experience with more than 900 pediatric patients
reported in the literature or to the manufacturer who were treated with INDOCIN
Capsules, side effects in pediatric patients were comparable to those reported
in adults. Experience in pediatric patients has been confined to the use of
INDOCIN Capsules.
If a decision is made to use indomethacin for pediatric
patients two years of age or older, such patients should be monitored closely
and periodic assessment of liver function is recommended. There have been cases
of hepatotoxicity reported in pediatric patients with juvenile rheumatoid
arthritis, including fatalities. If indomethacin treatment is instituted, a
suggested starting dose is 1-2 mg/kg/day given in divided doses. Maximum daily
dosage should not exceed 3 mg/kg/day or 150-200 mg/day, whichever is less.
Limited data are available to support the use of a maximum daily dosage of 4
mg/kg/day or 150- 200 mg/day, whichever is less. As symptoms subside, the total
daily dosage should be reduced to the lowest level required to control
symptoms, or the drug should be discontinued.
Geriatric Use
Elderly patients, compared to younger patients, are at
greater risk for NSAID-associated serious cardiovascular, gastrointestinal,
and/or renal adverse reactions. If the anticipated benefit for the elderly patient
outweighs these potential risks, start dosing at the low end of the dosing
range, and monitor patients for adverse effects [see WARNINGS AND PRECAUTIONS].
Indomethacin may cause confusion or rarely, psychosis [see ADVERSE REACTIONS]; physicians should remain alert to the possibility of
such adverse effects in the elderly.
Indomethacin and its metabolites are known to be
substantially excreted by the kidneys, and the risk of adverse reactions to
this drug may be greater in patients with impaired renal function. Because
elderly patients are more likely to have decreased renal function, use caution
in this patient population, and it may be useful to monitor renal function [see CLINICAL PHARMACOLOGY].