INDOCIN®

(INDOMETHACIN)
ORAL SUSPENSION

Cardiovascular Risk
• 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 (see WARNINGS).

Gastrointestinal Risk
• 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.)

DESCRIPTION

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.

1
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 is:

1 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

CLINICAL PHARMACOLOGY

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.

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INDOCIN has been shown to be an effective anti-inflammatory agent,
appropriate for long-term use in rheumatoid arthritis, ankylosing spondylitis, and
osteoarthritis.

INDOCIN affords relief of symptoms; it does not alter the progressive course of
the underlying disease.

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.

Indomethacin has 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

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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.

Indomethacin exists 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).

Indomethacin has been found effective in active stages of the following:

1. Moderate to severe rheumatoid arthritis including acute flares of chronic
disease.
2. Moderate to severe ankylosing spondylitis.
3. Moderate to severe osteoarthritis.
4. Acute painful shoulder (bursitis and/or tendinitis).
5. Acute gouty arthritis.

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CONTRAINDICATIONS

INDOCIN is contraindicated in patients with known hypersensitivity to

indomethacin or the excipients (see DESCRIPTION).

INDOCIN should not be given to patients who have experienced asthma,

urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe,
rarely fatal, anaphylactic/anaphylactoid reactions to NSAIDs have been reported
in such patients (see WARNINGS, - Anaphylactic/Anaphylactoid Reactions, and
PRECAUTIONS, - Preexisting Asthma).

INDOCIN is contraindicated for the treatment of peri-operative pain in the setting

of coronary artery bypass graft (CABG) surgery (see WARNINGS).

WARNINGS

Cardiovascular Effects

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

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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).

Hypertension

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.

In a 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
mechanisms.

Gastrointestinal Effects

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

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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.

NSAIDs should 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.

To minimize 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

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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
be considered.

Renal Effects

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 state.

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.

Anaphylactic/Anaphylactoid Reactions

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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.

Skin Reactions

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.

Pregnancy

In late pregnancy, as with other NSAIDs, INDOCIN should be avoided because it

may cause premature closure of the ductus arteriosus.

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. 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.

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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.

PRECAUTIONS

General

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.

Hepatic Effects

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

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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.

Hematological Effects

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.

Preexisting Asthma

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.

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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.
1. 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, Cardiovascular Effects).
2. 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).
3. 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.

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4. Patients should promptly report signs or symptoms of unexplained weight
gain or edema to their physicians.
5. 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.
6. 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).
7. In late pregnancy, as with other NSAIDs, INDOCIN should be avoided
because it may cause premature closure of the ductus arteriosus.

Laboratory Tests

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.

Drug Interactions

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

13
antagonist may result in further deterioration of renal function, including possible
acute renal failure, which is usually reversible.

Aspirin

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 therapy.

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 20%.

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.

Cyclosporine

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 monitored.

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Diflunisal

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.

Digoxin

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.

Diuretics

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.

INDOCIN 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.

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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.

Lithium

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.

Methotrexate

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.

NSAIDs

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.

Oral anticoagulants

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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.

Probenecid

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 patients.

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 effect.

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.

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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

Teratogenic Effects

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.

Nonteratogenic Effects

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.

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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 enterocolitis.

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.

Pediatric Use

Safety and effectiveness in pediatric patients 14 years of age and younger has
not been established.

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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 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 INDOCIN.

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

As with any NSAID, caution should be exercised in treating the elderly (65 years
and older) since advancing age appears to increase the possibility of adverse
reactions (see WARNINGS, Gastrointestinal Effects - Risk of Ulceration,
Bleeding, and Perforation and DOSAGE AND ADMINISTRATION). Elderly
patients seem to tolerate ulceration or bleeding less well than other individuals
and many spontaneous reports of fatal GI events are in this population (see
WARNINGS, Gastrointestinal Effects - Risk of Ulceration, Bleeding, and
Perforation).

20
Indomethacin may cause confusion or, rarely, psychosis (see ADVERSE
REACTIONS); physicians should remain alert to the possibility of such adverse
effects in the elderly.

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
(see WARNINGS, Renal Effects).

ADVERSE REACTIONS

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.

Incidence greater than 1% Incidence less than 1%

GASTROINTESTINAL

nausea* with or anorexia gastrointestinal bleeding without

without vomiting bloating (includes distension) obvious ulcer formation and

flatulence perforation of pre-existing
dyspepsia* (including
peptic ulcer sigmoid lesions (diverticulum,
indigestion, heartburn
gastroenteritis carcinoma, etc.) development
and
rectal bleeding of ulcerative colitis and
epigastric pain)
proctitis regional ileitis
diarrhea

21
Incidence greater than 1% Incidence less than 1%

abdominal distress or pain single or multiple ulcerations, ulcerative stomatitis

constipation including perforation and hemorrhage toxic hepatitis and jaundice
of the esophagus, stomach, (some fatal cases have been
duodenum or small and large reported)
intestines intestinal strictures
intestinal ulceration associated with (diaphragms)
stenosis and obstruction

CENTRAL NERVOUS SYSTEM

headache (11.7%) anxiety (includes nervousness) light-headedness

dizziness* muscle weakness syncope

vertigo involuntary muscle movements paresthesia

somnolence insomnia aggravation of epilepsy and

depression and fatigue muzziness parkinsonism

(including malaise and psychic disturbances including depersonalization

listlessness) psychotic episodes coma

mental confusion peripheral neuropathy
drowsiness convulsion
dysarthria

SPECIAL SENSES

tinnitus ocular — corneal deposits and retinal blurred vision

disturbances, including those of diplopia
the macula, have been reported in hearing disturbances, deafness
some patients on prolonged therapy
with INDOCIN

CARDIOVASCULAR

none hypertension congestive heart failure

hypotension arrhythmia; palpitations
tachycardia
chest pain

METABOLIC

none edema hyperglycemia

weight gain glycosuria
fluid retention hyperkalemia
flushing or sweating

INTEGUMENTARY

22
Incidence greater than 1% Incidence less than 1%

none pruritus exfoliative dermatitis

rash; urticaria erythema nodosum
petechiae or ecchymosis loss of hair
Stevens-Johnson syndrome
erythema multiforme
toxic epidermal necrolysis

HEMATOLOGIC

none leukopenia aplastic anemia

bone marrow depression hemolytic anemia
anemia secondary to obvious or occult agranulocytosis
gastrointestinal bleeding thrombocytopenic purpura
disseminated intravascular
coagulation

HYPERSENSITIVITY

none acute anaphylaxis dyspnea

acute respiratory distress asthma
rapid fall in blood pressure resembling purpura
a shock-like state angiitis
angioedema pulmonary edema
fever

GENITOURINARY

none hematuria BUN elevation

vaginal bleeding renal insufficiency, including
proteinuria renal failure
nephrotic syndrome
interstitial nephritis

MISCELLANEOUS

none epistaxis
breast changes, including enlargement
and tenderness, or gynecomastia

* Reactions occurring in 3% to 9% of patients treated with INDOCIN. (Those reactions occurring in less

than 3% of the patients are unmarked.)

23
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:

Cardiovascular: Thrombophlebitis

Hematologic: Although there have been several reports of leukemia, the

supporting information is weak

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).

OVERDOSAGE

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.

Treatment 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.

24
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).

After observing the response to initial therapy with INDOCIN, the dose and
frequency should be adjusted to suit an individual patient’s needs.

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.

Pediatric Use

INDOCIN ordinarily should not be prescribed for pediatric patients 14 years of

age and under (see PRECAUTIONS, Pediatric Use).

Adult Use

Dosage Recommendations for Active Stages of the Following:

1. 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

25
 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).
2. Acute painful shoulder (bursitis and/or tendinitis).
Initial Dose:
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.
3. 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

26
 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.

HOW SUPPLIED

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.

Storage

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)

(See the end of this Medication Guide for a list of prescription NSAID medicines.)

What is the most important information I should know about medicines called

non-steroidal anti-inflammatory drugs (NSAIDs)?

27
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”

• longer use

• smoking

• drinking alcohol

• older age

• 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 Drugs (NSAIDs)?

28
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 medicine:

• 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 doctor.

What are the possible side effects of Non-Steroidal Anti-Inflammatory Drugs

(NSAIDs)?

Serious side effects include: Other side effects include:

• heart attack • stomach pain

• stroke • constipation
• high blood pressure • diarrhea
• heart failure from body swelling (fluid • gas
retention) • heartburn
• kidney problems including kidney failure • nausea
• bleeding and ulcers in the stomach and • vomiting
intestine

29
Serious side effects include: Other side effects include:

• low red blood cells (anemia) • dizziness

• 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 • slurred speech

• chest pain • swelling of the face or throat
• weakness in one part or side of your body

Stop your NSAID medicine and call your healthcare provider right away if you
have any of the following symptoms:

• nausea • there is blood in your bowel

• more tired or weaker than usual movement or it is black and
• itching sticky like tar

• your skin or eyes look yellow • unusual weight gain

• stomach pain • skin rash or blisters with fever

• flu-like symptoms • swelling of the arms and legs,

• vomit blood 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.

30
 • 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.

NSAID medicines that need a prescription

Generic Name Tradename

Celecoxib Celebrex

Diclofenac Cataflam, Voltaren, Arthrotec (combined with misoprostol)

Diflunisal Dolobid

Etodolac Lodine, Lodine XL

Fenoprofen Nalfon, Nalfon 200

Flurbiprofen Ansaid

Ibuprofen Motrin, Tab-Profen, Vicoprofen* (combined with hydrocodone),

Combunox (combined with oxycodone)

Indomethacin Indocin, Indocin SR, Indo-Lemmon, Indomethegan

Ketoprofen Oruvail

Ketorolac Toradol

Mefenamic Ponstel
Acid

Meloxicam Mobic

Nabumetone Relafen

Naproxen Naprosyn, Anaprox, Anaprox DS, EC-Naprosyn, Naprelan,

Naprapac (copackaged with lansoprazole)

Oxaprozin Daypro

Piroxicam Feldene

Sulindac Clinoril

Tolmetin Tolectin, Tolectin DS, Tolectin 600

* 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 or stroke.

31
This Medication Guide has been approved by the U.S. Food and Drug
Administration.

4221C002

TE00

32
INDOCIN (indomethacin)
PRODUCT INFO

Product Code 42211-101 Dosage Form SUSPENSION

Route Of DEA
ORAL
Administration Schedule

INGREDIENTS
Name (Active Moiety) Type Strength

indomethacin (indomethacin) Active 25 MILLIGRAM In 5 MILLILITER

antifoam AF emulsion Inactive

pineapple coconut flavor Inactive

water Inactive

sodium hydroxide Inactive

hydrochloric acid Inactive

sorbitol solution Inactive

tragacanth Inactive

alcohol Inactive

sorbic acid Inactive

artificial mint flavor compound Inactive

IMPRINT INFORMATION
Characteristic Appearance Characteristic Appearance

Color Score

Shape Symbol

Imprint Code Coating

33
Size

PACKAGING
# NDC Package Description Multilevel Packaging
42211-
1 1 BOTTLE In 1 CARTON contains a BOTTLE
101-11
This package is contained within
1 237 MILLILITER In 1 BOTTLE
the CARTON (42211-101-11)

Revised: 09/2008 IROKO Pharmaceuticals, LLC

34