INDICATIONS AND USAGE Carefully consider the potential benefits and risks of indomethacin capsules, USP and other treatment options before deciding to use indomethacin.

Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals ( see Warnings: Gastrointestinal Bleeding, Ulceration, and Perforation ).

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.

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, including myocardial infarction (MI) and stroke, which can be fatal.

Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs.

The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease.

However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate.

Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment.

The increase in CV thrombotic risk has been observed most consistently at higher doses.

To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible.

Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms.

Patients should be informed about the symptoms of serious CV events and the steps to take if they occur.

There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use.

The concurrent use of aspirin and an NSAID, such as indomethacin, increases the risk of serious gastrointestinal (GI) events [see WARNINGS ].

Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke.

NSAIDs are contraindicated in the setting of CABG [see CONTRAINDICATIONS ].

Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment.

In this same cohort, the incidence of death in the first year post MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients.

Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up.

Avoid the use of indomethacin capsules in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events.

If indomethacin capsules are used in patients with a recent MI, monitor patients for signs of cardiac ischemia.

Hypertension NSAIDs, including indomethacin, can lead to onset of new hypertension or worsening of preexisting 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 indomethacin, 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.

Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients.

In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death.

Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs.

Use of indomethacin may blunt the CV effects of several therapeutic agents used to treat these medical conditions [e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers (ARBs)] [ see Precautions; Drug Interactions ].

Avoid the use of indomethacin capsules in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure.

If indomethacin capsules are used in patients with severe heart failure, monitor patients for signs of worsening heart failure.

Gastrointestinal Effects – Risk of Ulceration, Bleeding, and Perforation NSAIDs, including indomethacin, 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 indomethacin, intestinal ulceration has been associated with stenosis and obstruction.

Gastrointestinal bleeding without obvious ulcer formation and perforation of preexisting sigmoid lesions (diverticulum, carcinoma, etc.) has 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 without these risk factors.

Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAIDs therapy, concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking, use of alcohol, older age, and poor general health status.

Most postmarketing reports of fatal GI events occured in elderly or debilitated patients.

Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding.

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 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.

It has been reported that the addition of the potassium-sparing diuretic, triamterene, to a maintenance schedule of indomethacin resulted in reversible acute renal failure in two of four healthy volunteers.

Indomethacin and triamterene should not be administered together.

Increases in serum potassium concentration, including hyperkalemia, have been reported with use of indomethacin, 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 ].

Indomethacin and potassium-sparing diuretics each may be associated with increased serum potassium levels.

The potential effects of indomethacin and potassium-sparing diuretics on potassium kinetics and renal function should be considered when these agents are administered concurrently.

Advanced Renal Disease No information is available from controlled clinical studies regarding the use of indomethacin in patients with advanced renal disease.

Therefore, treatment with indomethacin is not recommended in these patients with advanced renal disease.

If indomethacin therapy must be initiated, close monitoring of the patient’s renal function is advisable.

Anaphylactic/Anaphylactoid Reactions As with other NSAIDs, anaphylactic/anaphylactoid reactions may occur in patients without known prior exposure to indomethacin.

Indomethacin 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 indomethacin, 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.

Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as indomethacin capsules.

Some of these events have been fatal or life-threatening.

DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling.

Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis.

Sometimes symptoms of DRESS may resemble an acute viral infection.

Eosinophilia is often present.

Because this disorder is variable in its presentation, other organ systems not noted here may be involved.

It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident.

If such signs or symptoms are present, discontinue indomethacin capsules and evaluate the patient immediately.

Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs, including indomethacin capsules, in pregnant women at about 30 weeks gestation and later.

NSAIDs including indomethacin capsules, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age.

Oligohydramnios/Neonatal Renal Impairment: Use of NSAIDs, including indomethacin capsules, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment.

These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation.

Oligohydramnios is often, but not always, reversible with treatment discontinuation.

Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation.

In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required.

If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit indomethacin capsules use to the lowest effective dose and shortest duration possible.

Consider ultrasound monitoring of amniotic fluid if indomethacin capsules treatment extends beyond 48 hours.

Discontinue indomethacin capsules if oligohydramnios occurs and follow up according to clinical practice [ see PRECAUTIONS ; Pregnancy ].

Ocular Effects Corneal deposits and retinal disturbances, including those of the macula, have been observed in some patients who had received prolonged therapy with indomethacin.

The prescribing physician should be alert to the possible association between the changes noted and indomethacin.

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: Indomethacin 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, indomethacin should be discontinued.

Indomethacin may cause drowsiness; therefore, patients should be cautioned about engaging in activities requiring mental alertness and motor coordination, such as driving a car.

Indomethacin may also cause headache.

Headache which persists despite dosage reduction requires cessation of therapy with indomethacin.

ADVERSE REACTIONS The adverse reactions for indomethacin capsules 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 indomethacin and these adverse reactions, some of which have been reported only rarely.

Incidence greater than 1% Incidence less than 1% GASTROINTESTINAL nausea * with or without vomiting dyspepsia * (including indigestion, heartburn and epigastric pain) diarrhea abdominal distress or pain constipation anorexia bloating (includes distension) flatulence peptic ulcer gastroenteritis rectal bleeding proctitis single or multiple ulcerations, including perforation and hemorrhage of the esophagus, stomach, duodenum or small and large intestines intestinal ulceration associated with stenosis and obstruction gastrointestinal bleeding without obvious ulcer formation and perforation of pre-existing sigmoid lesions (diverticulum, carcinoma, etc.) development of ulcerative colitis and regional ileitis ulcerative stomatitis toxic hepatitis and jaundice (some fatal cases have been reported) intestinal strictures (diaphragms) CENTRAL NERVOUS SYSTEM headache (11.7%) dizziness * vertigo somnolence depression and fatigue (including malaise and listlessness) anxiety (includes nervousness) muscle weakness involuntary muscle movements insomnia muzziness psychic disturbances including psychotic episodes mental confusion drowsiness light-headedness syncope paresthesia aggravation of epilepsy and parkinsonism depersonalization coma peripheral neuropathy convulsion dysarthria SPECIAL SENSES tinnitus ocular- corneal deposits and retinal disturbances, including those of the macula, have been reported in some patients on prolonged therapy with indomethacin blurred vision diplopia hearing disturbances, deafness CARDIOVASCULAR None hypertension hypotension tachycardia chest pain congestive heart failure arrhythmia; palpitations METABOLIC None edema weight gain fluid retention flushing or sweating hyperglycemia glycosuria hyperkalemia INTEGUMENTARY None pruritus rash; urticaria petechiae or ecchymosis exfoliative dermatitis erythema nodosum loss of hair Stevens-Johnson Syndrome erythema multiforme toxic epidermal necrolysis HEMATOLOGIC None leukopenia bone marrow depression anemia secondary to obvious or occult gastrointestinal bleeding aplastic anemia hemolytic anemia agranulocytosis thrombocytopenic purpura disseminated intravascular coagulation HYPERSENSITIVITY None acute anaphylaxis acute respiratory distress rapid fall in blood pressure resembling a shock-like state angioedema dyspnea asthma purpura angiitis pulmonary edema fever GENITOURINARY None hematuria vaginal bleeding proteinuria nephrotic syndrome interstitial nephritis BUN elevation renal insufficiency, including renal failure MISCELLANEOUS None epistaxis breast changes, including enlargement and tenderness, or gynecomastia * Reactions occurring in 3% to 9% of patients treated with indomethacin capsules.

(Those reactions occurring in less than 3% of the patients are unmarked.) 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 A β hemolytic streptococcus, has been described in persons treated with non-steroidal anti-inflammatory agents, including indomethacin, sometimes with fatal outcome [see also PRECAUTIONS , General ].