NSAIDs may cause an increased risk of serious cardiovascular
thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease
may be at a greater risk. (See WARNINGS.)
INDOCIN is contraindicated for the treatment of peri-operative
pain in the setting of coronary artery bypass graft (CABG) surgery
NSAIDs cause an increased risk of serious gastrointestinal adverse
events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events. (See WARNINGS.)
Suspension INDOCIN1 for oral use contains 25 mg of indomethacin per 5 mL, alcohol 1%, and sorbic acid 0.1% added as a preservative and the following inactive ingredients: antifoam
AF emulsion, flavors, purified water, sodium hydroxide or hydrochloric
acid to adjust pH, sorbitol solution, and tragacanth. Indomethacin is
a non-steroidal anti-inflammatory indole derivative designated chemically
as 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid. Indomethacin is practically insoluble
in water and sparingly soluble in alcohol. It has a pKa of 4.5 and
is stable in neutral or slightly acidic media and decomposes in strong
alkali. The suspension has a pH of 4.0-5.0. The structural formula
Registered trademark of MERCK & CO., Inc., Whitehouse Station, NJ U.S.A. and licensed to Iroko Pharmaceuticals, LLC, Philadelphia, PA, U.S.A. All rights reserved
INDOCIN is a non-steroidal anti-inflammatory drug
(NSAID) that exhibits antipyretic and analgesic properties. Its mode
of action, like that of other anti-inflammatory drugs, is not known.
However, its therapeutic action is not due to pituitary-adrenal stimulation.
INDOCIN is a potent inhibitor of prostaglandin synthesis in vitro. Concentrations are reached
during therapy which have been demonstrated to have an effect in vivo as well. Prostaglandins
sensitize afferent nerves and potentiate the action of bradykinin
in inducing pain in animal models. Moreover, prostaglandins are known
to be among the mediators of inflammation. Since indomethacin is an
inhibitor of prostaglandin synthesis, its mode of action may be due
to a decrease of prostaglandins in peripheral tissues.
INDOCIN has been shown to be an effective anti-inflammatory
agent, appropriate for long-term use in rheumatoid arthritis, ankylosing
spondylitis, and osteoarthritis.
relief of symptoms; it does not alter the progressive course of the
INDOCIN suppresses inflammation
in rheumatoid arthritis as demonstrated by relief of pain, and reduction
of fever, swelling and tenderness. Improvement in patients treated
with INDOCIN for rheumatoid arthritis has been demonstrated by a reduction
in joint swelling, average number of joints involved, and morning
stiffness; by increased mobility as demonstrated by a decrease in
walking time; and by improved functional capability as demonstrated
by an increase in grip strength. INDOCIN may enable the reduction
of steroid dosage in patients receiving steroids for the more severe
forms of rheumatoid arthritis. In such instances the steroid dosage
should be reduced slowly and the patients followed very closely for
any possible adverse effects.
been reported to diminish basal and CO2 stimulated cerebral
blood flow in healthy volunteers following acute oral and intravenous
administration. In one study after one week of treatment with
orally administered indomethacin, this effect on basal cerebral blood
flow had disappeared. The clinical significance of this effect has
not been established.
Capsules INDOCIN have
been found effective in relieving the pain, reducing the fever, swelling,
redness, and tenderness of acute gouty arthritis (see INDICATIONS AND USAGE).
Following single oral doses of Capsules INDOCIN 25 mg
or 50 mg, indomethacin is readily absorbed, attaining peak plasma
concentrations of about 1 and 2 mcg/mL, respectively, at about
2 hours. Orally administered Capsules INDOCIN are virtually 100% bioavailable,
with 90% of the dose absorbed within 4 hours. A single 50 mg
dose of Oral Suspension INDOCIN was found to be bioequivalent to a
50 mg INDOCIN capsule when each was administered with food.
Indomethacin is eliminated via renal excretion, metabolism,
and biliary excretion. Indomethacin undergoes appreciable enterohepatic
circulation. The mean half-life of indomethacin is estimated to be
about 4.5 hours. With a typical therapeutic regimen of 25 or
50 mg t.i.d., the steady-state plasma concentrations of indomethacin
are an average 1.4 times those following the first dose.
in the plasma as the parent drug and its desmethyl, desbenzoyl, and
desmethyldesbenzoyl metabolites, all in the unconjugated form. About
60 percent of an oral dosage is recovered in urine as drug and
metabolites (26 percent as indomethacin and its glucuronide),
and 33 percent is recovered in feces (1.5 percent as indomethacin).
About 99% of indomethacin is bound to protein in plasma
over the expected range of therapeutic plasma concentrations. Indomethacin
has been found to cross the blood-brain barrier and the placenta.
INDICATIONS AND USAGE
Carefully consider the potential benefits and risks
of INDOCIN and other treatment options before deciding to use INDOCIN.
Use the lowest effective dose for the shortest duration consistent
with individual patient treatment goals (see WARNINGS).
has been found effective in active stages of the following:
Moderate to severe rheumatoid arthritis including acute flares
of chronic disease.
contraindicated for the treatment of peri-operative pain in the setting
of coronary artery bypass graft (CABG) surgery (see WARNINGS).
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, myocardial
infarction, and stroke, which can be fatal. All NSAIDs, both COX-2
selective and nonselective, may have a similar risk. Patients with
known CV disease or risk factors for CV disease may be at greater
risk. To minimize the potential risk for an adverse CV event in patients
treated with an NSAID, the lowest effective dose should be used for
the shortest duration possible. Physicians and patients should remain
alert for the development of such events, even in the absence of previous
CV symptoms. Patients should be informed about the signs and/or 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
does increase the risk of serious GI events (see WARNINGS, Gastrointestinal Effects).
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 (see CONTRAINDICATIONS).
NSAIDs, including INDOCIN, can lead to onset of new
hypertension or worsening of pre-existing hypertension, either of
which may contribute to the increased incidence of CV events. Patients
taking thiazides or loop diuretics may have impaired response to these
therapies when taking NSAIDs. NSAIDs, including INDOCIN, should be
used with caution in patients with hypertension. Blood pressure (BP)
should be monitored closely during the initiation of NSAID treatment
and throughout the course of therapy.
Congestive Heart Failure and Edema
Fluid retention and edema have been observed in some
patients taking NSAIDs. INDOCIN should be used with caution in patients
with fluid retention or heart failure.
study of patients with severe heart failure and hyponatremia, INDOCIN
was associated with significant deterioration of circulatory hemodynamics,
presumably due to inhibition of prostaglandin dependent compensatory
Risk of Ulceration, Bleeding, and Perforation
NSAIDs, including INDOCIN, can 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 occur in approximately
1% of patients treated for 3-6 months, and in about 2-4% of patients
treated for one year. These trends continue with longer duration
of use, increasing the likelihood of developing a serious GI event
at some time during the course of therapy. However, even short-term
therapy is not without risk.
Rarely, in patients
taking INDOCIN, intestinal ulceration has been associated with stenosis
and obstruction. Gastrointestinal bleeding without obvious ulcer formation
and perforation of pre-existing sigmoid lesions (diverticulum, carcinoma,
etc.) have occurred. Increased abdominal pain in ulcerative colitis
patients or the development of ulcerative colitis and regional ileitis
have been reported to occur rarely.
be prescribed with extreme caution in those with prior history of
ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal
bleeding who use NSAIDs have a greater than 10‑fold
increased risk for developing a GI bleed compared to patients with
neither of these risk factors. Other factors that increase the risk
for GI bleeding in patients treated with NSAIDs include concomitant
use of oral corticosteroids or anticoagulants, longer duration of
NSAID therapy, smoking, use of alcohol, older age, and poor general
health status. Most spontaneous reports of fatal GI events are in
elderly or debilitated patients and therefore, special care should
be taken in treating this population.
the potential risk for an adverse GI event in patients treated with
an NSAID, the lowest effective dose should be used for the shortest
possible duration. Patients and physicians should remain alert for
signs and symptoms of GI ulceration and bleeding during NSAID therapy
and promptly initiate additional evaluation and treatment if a serious
GI adverse event is suspected. This should include discontinuation
of the NSAID until a serious GI adverse event is ruled out. For high
risk patients, alternate therapies that do not involve NSAIDs should
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 a nonsteroidal anti-inflammatory drug may cause a dose-dependent
reduction in prostaglandin formation and, secondarily, in renal blood
flow, which may precipitate over renal decompensation. Patients at
greatest risk of this reaction are those with impaired renal function,
heart failure, liver dysfunction, those taking diuretics and ACE inhibitors,
patients with volume depletion, and the elderly. Discontinuation of
NSAID therapy is usually followed by recovery to the pretreatment
Increases in serum potassium concentration,
including hyperkalemia, have been reported with use of INDOCIN, even
in some patients without renal impairment. In patients with normal
renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism
state (see PRECAUTIONS, Drug Interactions).
Advanced Renal Disease
No information is available from controlled clinical
studies regarding the use of INDOCIN in patients with advanced renal
disease. Therefore, treatment with INDOCIN is not recommended in these
patients with advanced renal disease. If INDOCIN therapy must be initiated,
close monitoring of the patient's renal function is advisable.
As with other NSAIDs, anaphylactic/anaphylactoid
reactions may occur in patients without known prior exposure to INDOCIN.
INDOCIN should not be given to patients with the aspirin triad. This
symptom complex typically occurs in asthmatic patients who experience
rhinitis with or without nasal polyps, or who exhibit severe, potentially
fatal bronchospasm after taking aspirin or other NSAIDs (see CONTRAINDICATIONS, and PRECAUTIONS - Preexisting Asthma). Emergency help should be sought in cases where an anaphylactic/anaphylactoid reaction occurs.
NSAIDs, including INDOCIN, can cause serious skin
adverse events such as exfoliative dermatitis, Stevens‑Johnson
Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be
fatal. These serious events may occur without warning. Patients should
be informed about the signs and symptoms of serious skin manifestations
and use of the drug should be discontinued at the first appearance
of skin rash or any other sign of hypersensitivity.
In late pregnancy, as with other NSAIDs, INDOCIN
should be avoided because it may cause premature closure of the ductus
Corneal deposits and retinal disturbances, including
those of the macula, have been observed in some patients who had received
prolonged therapy with INDOCIN. The prescribing physician should 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
where therapy is prolonged.
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. If severe
CNS adverse reactions develop, INDOCIN should be discontinued.
INDOCIN may cause drowsiness; therefore, patients should
be cautioned about engaging in activities requiring mental alertness
and motor coordination, such as driving a car. INDOCIN may also cause
headache. Headache which persists despite dosage reduction requires
cessation of therapy with INDOCIN.
INDOCIN cannot be expected to substitute for corticosteroids
or to treat corticosteroid insufficiency. Abrupt discontinuation of
corticosteroids may lead to disease exacerbation. Patients on prolonged
corticosteroid therapy should have their therapy tapered slowly if
a decision is made to discontinue corticosteroids.
The pharmacological activity of INDOCIN in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications
of presumed noninfectious, painful conditions.
Borderline elevations of one or more liver tests
may occur in up to 15% of patients taking NSAIDs including INDOCIN.
These laboratory abnormalities may progress, may remain unchanged,
or may be transient with continuing therapy. Notable elevations of
ALT or AST (approximately three or more times the upper limit of normal)
have been reported in approximately 1% of patients in clinical trials
with NSAIDs. In addition, rare cases of severe hepatic reactions,
including jaundice and fatal fulminant hepatitis, liver necrosis and
hepatic failure, some of them with fatal outcomes have been reported.
A patient with symptoms and/or signs suggesting liver
dysfunction, or in whom an abnormal liver test has occurred, should
be evaluated for evidence of the development of a more severe hepatic
reaction while on therapy with INDOCIN. If clinical signs and symptoms
consistent with liver disease develop, or if systemic manifestations
occur (e.g., eosinophilia, rash, etc.), INDOCIN should be discontinued.
Anemia is sometimes seen in patients receiving NSAIDs,
including INDOCIN. This may be due to fluid retention, occult or gross
GI blood loss, or an incompletely described effect upon erythropoiesis.
Patients on long-term treatment with NSAIDs, including INDOCIN, should
have their hemoglobin or hematocrit checked if they exhibit any signs
or symptoms of anemia.
NSAIDs inhibit platelet
aggregation and have been shown to prolong bleeding time in some patients.
Unlike aspirin, their effect on platelet function is quantitatively
less, of shorter duration, and reversible. Patients receiving INDOCIN
who may be adversely affected by alterations in platelet function,
such as those with coagulation disorders or patients receiving anticoagulants,
should be carefully monitored.
Patients with asthma may have aspirin-sensitive asthma.
The use of aspirin in patients with aspirin-sensitive asthma has been
associated with severe bronchospasm which can be fatal. Since cross
reactivity, including bronchospasm, between aspirin and other nonsteroidal
anti-inflammatory drugs has been reported in such aspirin-sensitive
patients, INDOCIN should not be administered to patients with this
form of aspirin sensitivity and should be used with caution in patients
with preexisting asthma.
Information for Patients
Patients should be informed
of the following information before initiating therapy with an NSAID
and periodically during the course of ongoing therapy. Patients should
also be encouraged to read the NSAID Medication Guide that accompanies
each prescription dispensed.
INDOCIN, like other NSAIDs, may cause serious CV side effects,
such as MI or stroke, which may result in hospitalization and even
death. Although serious CV events can occur without warning symptoms,
patients should be alert for the signs and symptoms of chest pain,
shortness of breath, weakness, slurring of speech, and should ask
for medical advice when observing any indicative sign or symptoms.
Patients should be apprised of the importance of this follow-up (see WARNINGS,
INDOCIN, like other NSAIDs, can cause GI discomfort and, rarely,
serious GI side effects, such as ulcers and bleeding, which may result
in hospitalization and even death. Although serious GI tract ulcerations
and bleeding can occur without warning symptoms, patients should be
alert for the signs and symptoms of ulcerations and bleeding, and
should ask for medical advice when observing any indicative sign or
symptoms including epigastric pain, dyspepsia, melena, and hematemesis.
Patients should be apprised of the importance of this follow-up (see WARNINGS, Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation).
INDOCIN, like other NSAIDs, can cause serious skin side effects
such as exfoliative dermatitis, SJS, and TEN, which may result in
hospitalizations and even death. Although serious skin reactions may
occur without warning, patients should be alert for the signs and
symptoms of skin rash and blisters, fever, or other signs of hypersensitivity
such as itching, and should ask for medical advice when observing
any indicative signs or symptoms. Patients should be advised to stop
the drug immediately if they develop any type of rash and contact
their physicians as soon as possible.
Patients should promptly report signs or symptoms of unexplained
weight gain or edema to their physicians.
Patients should be informed of the warning signs and symptoms
of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice,
right upper quadrant tenderness, and “flu-like” symptoms).
If these occur, patients should be instructed to stop therapy and
seek immediate medical therapy.
Patients should be informed of the signs of an anaphylactic/anaphylactoid
reaction (e.g. difficulty breathing, swelling of the face or throat).
If these occur, patients should be instructed to seek immediate emergency
help (see WARNINGS).
In late pregnancy, as with other NSAIDs, INDOCIN should be avoided
because it may cause premature closure of the ductus arteriosus.
Because serious GI tract ulcerations and bleeding
can occur without warning symptoms, physicians should monitor for
signs or symptoms of GI bleeding. Patients on long-term treatment
with NSAIDs should have their CBC and a chemistry profile checked
periodically. If clinical signs and symptoms consistent with liver
or renal disease develop, systemic manifestations occur (e.g., eosinophilia,
rash, etc.) or if abnormal liver tests persist or worsen, INDOCIN
should be discontinued.
ACE-Inhibitors and Angiotensin II Antagonists
Reports suggest that NSAIDs may diminish the antihypertensive
effect of ACE-inhibitors and angiotensin II antagonists. INDOCIN
can reduce the antihypertensive effects of captopril and losartan.
These interactions should be given consideration in patients taking
NSAIDs concomitantly with ACE-inhibitors or angiotensin II antagonists.
In some patients with compromised renal function, the co-administration
of an NSAID and an ACE-inhibitor or an angiotensin II antagonist
may result in further deterioration of renal function, including possible
acute renal failure, which is usually reversible.
When INDOCIN is administered with aspirin, its protein
binding is reduced, although the clearance of free INDOCIN is not
altered. The clinical significance of this interaction is not known.
The use of INDOCIN in conjunction with aspirin or other
salicylates is not recommended. Controlled clinical studies have shown
that the combined use of INDOCIN and aspirin does not produce any
greater therapeutic effect than the use of INDOCIN alone. In a clinical
study of the combined use of INDOCIN and aspirin, the incidence of
gastrointestinal side effects was significantly increased with combined
In a study in normal volunteers, it
was found that chronic concurrent administration of 3.6 g of
aspirin per day decreases indomethacin blood levels approximately
Beta-adrenoceptor blocking agents
Blunting of the antihypertensive effect of beta‑adrenoceptor
blocking agents by non-steroidal anti-inflammatory drugs including
INDOCIN has been reported. Therefore, when using these blocking agents
to treat hypertension, patients should be observed carefully in order
to confirm that the desired therapeutic effect has been obtained.
Administration of non-steroidal anti-inflammatory
drugs concomitantly with cyclosporine has been associated with an
increase in cyclosporine-induced toxicity, possibly due to decreased
synthesis of renal prostacyclin. NSAIDs should be used with caution
in patients taking cyclosporine, and renal function should be carefully
In normal volunteers receiving indomethacin, the
administration of diflunisal decreased the renal clearance and significantly
increased the plasma levels of indomethacin. In some patients, combined
use of INDOCIN and diflunisal has been associated with fatal gastrointestinal
hemorrhage. Therefore, diflunisal and INDOCIN should not be used concomitantly.
INDOCIN given concomitantly with digoxin has been
reported to increase the serum concentration and prolong the half‑life
of digoxin. Therefore, when INDOCIN and digoxin are used concomitantly,
serum digoxin levels should be closely monitored.
In some patients, the administration of INDOCIN can
reduce the diuretic, natriuretic, and antihypertensive effects of
loop, potassium-sparing, and thiazide diuretics. This response has
been attributed to inhibition of renal prostaglandin synthesis.
INDOCIN reduces basal plasma renin activity (PRA), as
well as those elevations of PRA induced by furosemide administration,
or salt or volume depletion. These facts should be considered when
evaluating plasma renin activity in hypertensive patients.
It has been reported that the addition of triamterene
to a maintenance schedule of INDOCIN resulted in reversible acute
renal failure in two of four healthy volunteers. INDOCIN and triamterene
should not be administered together.
and potassium-sparing diuretics each may be associated with increased
serum potassium levels. The potential effects of INDOCIN and potassium-sparing
diuretics on potassium kinetics and renal function should be considered
when these agents are administered concurrently.
Most of the above effects concerning diuretics have been attributed,
at least in part, to mechanisms involving inhibition of prostaglandin
synthesis by INDOCIN.
During concomitant therapy
with NSAIDs, the patient should be observed closely for signs of renal
failure (see WARNINGS,
Renal Effects), as well as to assure diuretic efficacy.
Capsules INDOCIN 50 mg t.i.d. produced a clinically
relevant elevation of plasma lithium and reduction in renal lithium
clearance in psychiatric patients and normal subjects with steady
state plasma lithium concentrations. This effect has been attributed
to inhibition of prostaglandin synthesis. As a consequence, when NSAIDs
and lithium are given concomitantly, the patient should be carefully
observed for signs of lithium toxicity. (Read circulars for lithium
preparations before use of such concomitant therapy.) In addition,
the frequency of monitoring serum lithium concentration should be
increased at the outset of such combination drug treatment.
NSAIDs have been reported to competitively inhibit
methotrexate accumulation in rabbit kidney slices. This may indicate
that they could enhance the toxicity of methotrexate. Caution should
be used when NSAIDs are administered concomitantly with methotrexate.
The concomitant use of INDOCIN with other NSAIDs
is not recommended due to the increased possibility of gastrointestinal
toxicity, with little or no increase in efficacy.
Clinical studies have shown that INDOCIN does not
influence the hypoprothrombinemia produced by anticoagulants. However,
when any additional drug, including INDOCIN, is added to the treatment
of patients on anticoagulant therapy, the patients should be observed
for alterations of the prothrombin time. In post-marketing experience,
bleeding has been reported in patients on concomitant treatment with
anticoagulants and INDOCIN. Caution should be exercised when INDOCIN
and anticoagulants are administered concomitantly. The effects of
warfarin and NSAIDs on GI bleeding are synergistic, such that
users of both drugs together have a risk of serious GI bleeding higher
than users of either drug alone.
When INDOCIN is given to patients receiving probenecid,
the plasma levels of indomethacin are likely to be increased. Therefore,
a lower total daily dosage of INDOCIN may produce a satisfactory therapeutic
effect. When increases in the dose of INDOCIN are made, they should
be made carefully and in small increments.
Drug/Laboratory Test Interactions
False-negative results in the dexamethasone suppression
test (DST) in patients being treated with INDOCIN have been reported.
Thus, results of the DST should be interpreted with caution in these
Carcinogenesis, Mutagenesis, Impairment of Fertility
In an 81‑week chronic oral toxicity study
in the rat at doses up to 1 mg/kg/day, indomethacin had no tumorigenic
Indomethacin produced no neoplastic
or hyperplastic changes related to treatment in carcinogenic studies
in the rat (dosing period 73-110 weeks) and the mouse (dosing
period 62-88 weeks) at doses up to 1.5 mg/kg/day.
Indomethacin did not have any mutagenic effect in in vitro bacterial tests (Ames
test and E. coli with
or without metabolic activation) and a series of in vivo tests including the host-mediated
assay, sex-linked recessive lethals in Drosophila, and the micronucleus test in mice.
Indomethacin at dosage levels up to 0.5 mg/kg/day
had no effect on fertility in mice in a two generation reproduction
study or a two litter reproduction study in rats.
Pregnancy Category C
Teratogenic 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 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) have described
maternal toxicity and death, increased fetal resorptions, and fetal
malformations. Comparable studies in rodents using high doses of aspirin
have shown similar maternal and fetal effects. However, animal reproduction
studies are not always predictive of human response. There are no
adequate and well-controlled studies in pregnant women.
INDOCIN should be used during pregnancy only if the potential
benefit justifies the potential risk to the fetus.
Because of the known effects of non-steroidal anti-inflammatory
drugs on the fetal cardiovascular system (closure of ductus arteriosus),
use during pregnancy (particularly late pregnancy) should be avoided.
The known effects of indomethacin and other drugs of this
class on the human fetus during the third trimester of pregnancy include:
constriction of the ductus arteriosus prenatally, tricuspid incompetence,
and pulmonary hypertension; non-closure of the ductus arteriosus postnatally
which may be resistant to medical management; myocardial degenerative
changes, platelet dysfunction with resultant bleeding, intracranial
bleeding, renal dysfunction or failure, renal injury/dysgenesis which
may result in prolonged or permanent renal failure, oligohydramnios,
gastrointestinal bleeding or perforation, and increased risk of necrotizing
In rats and mice, 4.0 mg/kg/day
given during the last three days of gestation caused a decrease in
maternal weight gain and some maternal and fetal deaths. An increased
incidence of neuronal necrosis in the diencephalon in the live-born
fetuses was observed. At 2.0 mg/kg/day, no increase in neuronal necrosis
was observed as compared to the control groups. Administration of
0.5 or 4.0 mg/kg/day during the first three days of life did not cause
an increase in neuronal necrosis at either dose level.
Labor and Delivery
In rat studies with NSAIDs, as with other drugs known
to inhibit prostaglandin synthesis, an increased incidence of dystocia,
delayed parturition, and decreased pup survival occurred. The effects
of INDOCIN on labor and delivery in pregnant women are unknown.
Use in Nursing Mothers
Indomethacin is excreted in the milk of lactating mothers.
INDOCIN is not recommended for use in nursing mothers.
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.
with more than 900 pediatric patients reported in the literature or
to the manufacturer who were treated with Capsules INDOCIN, side effects
in pediatric patients were comparable to those reported in adults.
Experience in pediatric patients has been confined to the use of 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.
Indomethacin may cause confusion or, rarely,
psychosis (see ADVERSE REACTIONS); physicians
should remain alert to the possibility of such adverse effects in
This drug is known to be substantially
excreted by the kidney and the risk of toxic reactions to this drug
may be greater in patients with impaired renal function. Because elderly
patients are more likely to have decreased renal function, care should
be taken in dose selection and it may be useful to monitor renal function
The adverse reactions for Capsules INDOCIN listed in the following
table have been arranged into two groups: (1) incidence greater than
1%; and (2) incidence less than 1%. The incidence for group (1) was
obtained from 33 double-blind controlled clinical trials reported
in the literature (1,092 patients). The incidence for group (2) was
based on reports in clinical trials, in the literature, and on voluntary
reports since marketing. The probability of a causal relationship
exists between INDOCIN and these adverse reactions, some of which
have been reported only rarely.
The adverse reactions reported with Capsules INDOCIN may
also occur with use of the suspension.
and fatigue (including malaise and listlessness)
anxiety (includes nervousness)
psychic disturbances including psychotic
aggravation of epilepsy and parkinsonism
ocular — corneal deposits
and retinal disturbances, including those
of the macula, have been reported in some patients on prolonged therapy with
hearing disturbances, deafness
congestive heart failure
flushing or sweating
petechiae or ecchymosis
loss of hair
toxic epidermal necrolysis
bone marrow depression
anemia secondary to
obvious or occult gastrointestinal bleeding
acute respiratory distress
fall in blood pressure resembling a shock-like
renal insufficiency, including renal failure
breast changes, including enlargement and
tenderness, or gynecomastia
Causal relationship unknown: Other reactions have been reported but occurred under circumstances
where a causal relationship could not be established. However, in
these rarely reported events, the possibility cannot be excluded.
Therefore, these observations are being listed to serve as alerting
information to physicians:
there have been several reports of leukemia, the supporting information
Genitourinary: Urinary frequency
A rare occurrence of fulminant
necrotizing fasciitis, particularly in association with Group Aβ
hemolytic streptococcus, has been described in persons treated with
non-steroidal anti-inflammatory agents, including indomethacin, sometimes
with fatal outcome (see also PRECAUTIONS, General).
The following symptoms may be observed following
overdosage: nausea, vomiting, intense headache, dizziness, mental
confusion, disorientation, or lethargy. There have been reports of
paresthesias, numbness, and convulsions.
is symptomatic and supportive. The stomach should be emptied as quickly
as possible if the ingestion is recent. If vomiting has not occurred
spontaneously, the patient should be induced to vomit with syrup of
ipecac. If the patient is unable to vomit, gastric lavage should be
performed. Once the stomach has been emptied, 25 or 50 g of activated
charcoal may be given. Depending on the condition of the patient,
close medical observation and nursing care may be required. The patient
should be followed for several days because gastrointestinal ulceration
and hemorrhage have been reported as adverse reactions of indomethacin.
Use of antacids may be helpful.
The oral LD50 of indomethacin in mice and rats (based on 14 day mortality
response) was 50 and 12 mg/kg, respectively.
DOSAGE AND ADMINISTRATION
Carefully consider the potential benefits and risks
of INDOCIN and other treatment options before deciding to use INDOCIN.
Use the lowest effective dose for the shortest duration consistent
with individual patient treatment goals (see WARNINGS).
observing the response to initial therapy with INDOCIN, the dose and
frequency should be adjusted to suit an individual patient's
Oral Suspension INDOCIN contains 25 mg of indomethacin per 5 mL.
Adverse reactions appear to correlate with the size of the dose of INDOCIN in most patients but not all. Therefore, every effort should be made to determine the smallest effective dosage for the individual patient.
Dosage Recommendations for Active Stages of the Following:
Moderate to severe rheumatoid arthritis including acute flares
of chronic disease; moderate to severe ankylosing spondylitis; and
moderate to severe osteoarthritis. Suggested Dosage: INDOCIN 25 mg (5 mL) b.i.d. or t.i.d. If this is well tolerated, increase the daily dosage by 25 mg (5 mL) or by 50 mg (10 mL), if required by continuing symptoms, at weekly intervals until a satisfactory response is obtained or until a total daily dose of 150-200 mg (30 – 40 mL) is reached. DOSES ABOVE THIS AMOUNT GENERALLY DO NOT INCREASE THE EFFECTIVENESS OF THE DRUG.
In patients who have persistent night pain and/or morning stiffness, the giving of a large portion, up to a maximum of 100 mg (20 mL), of
the total daily dose at bedtime, may be helpful in affording relief. The total daily dose should not
exceed 200 mg (40 mL). In acute flares of chronic rheumatoid arthritis, it may be necessary to increase the dosage by 25 mg (5 mL) or, if required, by 50 mg (10 mL) daily.
If minor adverse effects develop as the dosage is increased, reduce the dosage rapidly to a tolerated dose and OBSERVE THE PATIENT CLOSELY.
If severe adverse reactions occur, STOP THE DRUG. After the acute phase of the disease is under control, an attempt to reduce the daily dose should be made repeatedly until the patient is receiving the smallest effective dose or the drug is discontinued. Careful instructions to, and observations of, the individual patient are essential to the
prevention of serious, irreversible, including fatal, adverse reactions.
As advancing years appear to increase the possibility
of adverse reactions, INDOCIN should be used with greater care in
the elderly (see PRECAUTIONS, Geriatric Use).
75-150 mg (15-30 mL) daily in 3 or
4 divided doses.
The drug should be discontinued
after the signs and symptoms of inflammation have been controlled
for several days. The usual course of therapy is 7-14 days.
Acute gouty arthritis. Suggested Dose: INDOCIN
50 mg (10 mL) t.i.d. until pain is tolerable. The dose should then be rapidly reduced to complete cessation of the drug. Definite relief of pain has been reported within 2 to 4 hours. Tenderness and heat usually subside in 24 to 36 hours, and swelling gradually
disappears in 3 to 5 days.
Oral Suspension INDOCIN, 25 mg per 5 mL, is an off-white suspension
with a pineapple coconut mint flavor. It is supplied as follows:
NDC 42211-101-11 in bottles of 237 mL.
Store Oral Suspension INDOCIN below 30°C (86°F).
Avoid temperatures above 50°C (122°F). Protect from freezing.
Oral Suspension INDOCIN® is manufactured by: MERCK & CO., INC., Whitehouse Station, NJ 08889, USA
Distributed by: IROKO Pharmaceuticals, LLC Philadelphia, PA 19112
Rev 10/08 4221C002 TE00
Medication Guide for Non-Steroidal
Anti-Inflammatory Drugs (NSAIDs)
What is the most important information
I should know about medicines called non-steroidal anti-inflammatory drugs (NSAIDs)?
NSAID medicines may
increase the chance of a heart attack or stroke that can lead to death. This chance increases:
with longer use of NSAID medicines
in people who have heart disease
NSAID medicines should
never be used right before or after a heart surgery called a “coronary
artery bypass graft (CABG).”
NSAID medicines can cause ulcers and
bleeding in the stomach and intestines at any time during treatment.
Ulcers and bleeding:
can happen without warning symptoms
may cause death
The chance of a person
getting an ulcer or bleeding increases with:
taking medicines called “corticosteroids” and “anticoagulants”
having poor health
NSAID medicines should
only be used:
exactly as prescribed
at the lowest dose possible for your treatment
for the shortest time needed
What are Non-Steroidal Anti-Inflammatory
NSAID medicines are used to treat pain and redness,
swelling, and heat (inflammation) from medical conditions such as:
different types of arthritis
menstrual cramps and other types of short-term pain
Who should not take a Non-Steroidal
Anti-Inflammatory Drug (NSAID)?
Do not take an NSAID
if you had an asthma attack, hives, or other allergic reaction
with aspirin or any other NSAID medicine
for pain right before or after heart bypass surgery
Tell your healthcare provider:
about all of your medical conditions.
about all of the medicines you take. NSAIDs and some other medicines
can interact with each other and cause serious side effects. Keep a list of your medicines to show to your healthcare
provider and pharmacist.
if you are pregnant. NSAID medicines
should not be used by pregnant women late in their pregnancy.
if you are breastfeeding. Talk to your
What are the possible side effects
of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
Serious side effects include:
Other side effects include:
high blood pressure
heart failure from body swelling (fluid retention)
kidney problems including kidney failure
bleeding and ulcers in the stomach and intestine
low red blood cells (anemia)
life-threatening skin reactions
life-threatening allergic reactions
liver problems including liver failure
asthma attacks in people who have asthma
Get emergency help right away if
you have any of the following symptoms:
shortness of breath or trouble breathing
weakness in one part or side of your body
swelling of the face or throat
Stop your NSAID medicine and call
your healthcare provider right away if you have any of the following
more tired or weaker than usual
your skin or eyes look yellow
there is blood in your bowel movement or it is black and sticky
unusual weight gain
skin rash or blisters with fever
swelling of the arms and legs, hands and feet
These are not all the side effects with NSAID medicines.
Talk to your healthcare provider or pharmacist for more information
about NSAID medicines.
Other information about Non-Steroidal
Anti-Inflammatory Drugs (NSAIDs)
Aspirin is an NSAID medicine but it does not increase the chance
of a heart attack. Aspirin can cause bleeding in the brain, stomach,
and intestines. Aspirin can also cause ulcers in the stomach and intestines.
Some of these NSAID medicines are sold in lower doses without
a prescription (over-the-counter). Talk to your healthcare provider
before using over-the-counter NSAIDs for more than 10 days.
Vicoprofen contains the
same dose of ibuprofen as over-the-counter (OTC) NSAIDs, and is usually
used for less than 10 days to treat pain. The OTC NSAID label warns
that long term continuous use may increase the risk of heart attack
Cataflam, Voltaren, Arthrotec (combined
Lodine, Lodine XL
Nalfon, Nalfon 200
Motrin, Tab-Profen, Vicoprofen* (combined with hydrocodone), Combunox (combined
Indocin, Indocin SR, Indo-Lemmon, Indomethegan
Naprosyn, Anaprox, Anaprox DS, EC-Naprosyn, Naprelan, Naprapac (copackaged with lansoprazole)
Tolectin, Tolectin DS, Tolectin 600
This Medication Guide has been approved by the U.S. Food and Drug Administration.
HUMAN PRESCRIPTION DRUG
Item Code (Source)
Route of Administration
Name (Active Moiety)
25 MILLIGRAM In 5 MILLILITER
antifoam AF emulsion
pineapple coconut flavor
artificial mint flavor compound
contains a BOTTLE
This package is contained within the CARTON (42211-101-11)