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INDOTEC®
Technilab
Indomethacin
Nonsteroidal Anti-inflammatory - Analgesic
 
Action And Clinical Pharmacology: Indomethacin is a nonsteroidal anti-inflammatory drug with marked analgesic, and antipyretic properties. It has a unique chemical structure, which differentiates it from the salicylates, corticosteroids, phenylbutazone-like compounds and colchicine. Unlike corticosteroids, it has no effect on pituitary or adrenal function.

Indomethacin is a potent inhibitor of prostaglandin synthesis in vitro. Concentrations are reached during therapy which have been demonstrated to have an in vivo effect as well.

Although indomethacin does not alter the course of the underlying disease, it has been found effective to relieve pain, reduce fever, swelling and tenderness, and increase mobility in patients with rheumatic diseases, including rheumatoid arthritis, ankylosing spondylitis, osteoarthritis and gout.

Pharmacokinetics: In man, indomethacin is readily absorbed, attaining peak plasma concentrations of about 1 and 2 µg/mL at approximately 2 hours following single oral doses of 25 and 50 mg, respectively. Ninety percent of the orally administered indomethacin is absorbed within 4 hours. The suppository formulation is more rapidly and completely absorbed than the oral dose of indomethacin. Thus, Cmax after rectal administration is lower than after oral dosing. 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 on average 1.4 times those following the first dose.

Indomethacin exists in the plasma as the parent drug and its desmethyl, desbenzoyl, and desmethyl-desbenzoyl metabolites, all in the unconjugated form. About 60% of an oral dosage is recovered in urine as drug and metabolites (26% as indomethacin and its glucuronide), and 33% is recovered in feces (1.5% as indomethacin).

About 90% of indomethacin is bound to protein in plasma over the expected range of therapeutic plasma concentration.

Indications And Clinical Uses: Indomethacin is not a simple analgesic, and its use should be limited to the conditions listed below, particularly those cases not responding to conservative measures.

Indomethacin has been found effective in the symptomatic treatment of: selected cases of rheumatoid arthritis; ankylosing (rheumatoid) spondylitis; gout; selected cases of severe osteoarthritis, including degenerative disease of the hip.

In these conditions indomethacin may on occasion replace other commonly used agents such as corticosteroids, salicylates, phenylbutazone-like compounds and colchicine.

Indomethacin suppositories are for those patients in whom rectal administration is preferred.

Rheumatoid Arthritis: Indomethacin may be used singly or in combination with other agents. However, it should not be used as a drug of first choice because of the adverse reactions that may occur with its use.

Best results (relief of pain, tenderness, swelling and stiffness) have been obtained in the acute episodes of the disease. However, in many patients with chronic rheumatoid arthritis, indomethacin will produce a significant lessening of pain and stiffness within 48 hours. In other patients, treatment must be continued longer before significant subjective relief or objective evidence of decreased joint swelling and tenderness occur. In some cases of chronic rheumatoid arthritis, it may be necessary to continue treatment for at least a month before concluding that it has not produced significant benefit. Use of indomethacin may enable reduction of steroid dosage in patients receiving corticosteroids. In such instances, the steroid dosage should be reduced slowly.

Ankylosing (Rheumatoid) Spondylitis: Indomethacin frequently produces marked relief of pain and improved motion of the spine within 3 to 10 days.

Osteoarthritis: Indomethacin should be used in those cases of severe osteoarthritis which do not respond to treatment with other drugs such as the salicylates. In many cases prompt relief of pain is obtained.

Degenerative Joint Disease (Osteoarthritis) of the Hip: Indomethacin may be used to provide relief of pain and increased range of motion in patients with degenerative joint disease of the hip.

Gout: In acute attacks of gout the response to indomethacin is usually rapid and often dramatic. Marked reduction of pain may be obtained within 2 to 4 hours. Tenderness and heat subside within 24 to 36 hours, and swelling decreases over a 3- to 5-day period.

Contra-Indications: Active peptic ulcer, a history of recurrent ulceration or active inflammatory disease of the gastrointestinal system.

Known or suspected hypersensitivity to the drug or other NSAIDs. The potential for cross-reactivity between different NSAIDs must be kept in mind.

Indomethacin should not be used in patients with the complete or partial syndrome of nasal polyps, or in whom asthma, anaphylaxis, urticaria, rhinitis or other allergic manifestations are precipitated by ASA or other NSAIDs. Fatal anaphylactoid reactions have occurred in such individuals. As well, individuals with the above medical problems are at risk of a severe reaction even if they have taken NSAIDs in the past without any adverse effects.

Significant hepatic impairment or active liver disease.

Severely impaired or deteriorating renal function (creatinine clearance <30 mL/minute). Individuals with lesser degrees of renal impairment are at risk of deterioration of their renal function when prescribed NSAIDs and must be monitored.

Indomethacin is not recommended for use with other NSAIDs because of the absence of any evidence demonstrating synergistic benefits and the potential for additive side effects.

Indomethacin suppositories are contraindicated in subjects with a recent history of rectal bleeding or proctitis.

Manufacturers' Warnings In Clinical States: Gastrointestinal System: Serious gastrointestinal toxicity, such as peptic ulceration, perforation and gastrointestinal bleeding, sometimes severe and occasionally fatal can occur at any time, with or without symptoms in patients treated with NSAIDs including indomethacin.

Minor upper gastrointestinal problems, such as dyspepsia, are common, usually developing early in therapy. Physicians should remain alert for ulceration and bleeding in patients treated with NSAIDs, even in the absence of previous gastrointestinal tract symptoms.

In patients observed in clinical trials of such agents, symptomatic upper gastrointestinal ulcers, gross bleeding, or perforation appear to occur in approximately 1% of patients treated for 3 to 6 months and in about 2 to 4% of patients treated for 1 year. The risk continues beyond 1 year and possibly increases.

The incidence of these complications increases with increasing dose.

Indomethacin should be given under close medical supervision to patients prone to gastrointestinal tract irritation, particularly those with a history of peptic ulcer, diverticulosis or other inflammatory disease of the gastrointestinal tract such as ulcerative colitis and Crohn's disease. In these cases, the physician must weigh the benefits of treatment against the possible hazards.

Physicians should inform patients about the signs and/or symptoms of serious gastrointestinal toxicity and instruct them to contact a physician immediately if they experience persistent dyspepsia or other symptoms or signs suggestive of gastrointestinal ulceration or bleeding.

Because serious gastrointestinal tract ulceration and bleeding can occur without warning symptoms, physicians should follow chronically treated patients by checking their hemoglobin periodically and by being vigilant for the signs and symptoms of ulceration and bleeding and should inform the patients of the importance of this follow-up.

If ulceration is suspected or confirmed, or if gastrointestinal bleeding occurs, indomethacin should be discontinued immediately, appropriate treatment instituted and the patient monitored closely.

No studies, to date, have identified any group of patients not at risk of developing ulceration and bleeding. A prior history of serious gastrointestinal events and other factors such as excess alcohol intake, smoking, age, female gender and concomitant oral steroid and anticoagulant use have been associated with increased risk.

Studies to date show that all NSAIDs can cause gastrointestinal tract adverse events. Although existing data does not clearly identify differences in risk between various NSAIDs, this may be shown in the future.

Geriatrics: Patients older than 65 years and frail or debilitated patients are most susceptible to a variety of adverse reactions from NSAIDs; the incidence of these adverse reactions increases with dose and duration of treatment. In addition, these patients are less tolerant to ulceration and bleeding. Most reports of fatal gastrointestinal events are in this population. Older patients are also at risk of lower esophageal ulceration and bleeding.

For such patients, consideration should be given to a starting dose lower than the one usually recommended, with individual adjustment when necessary and under close supervision (see Precautions).

Cross-sensitivity: Patients sensitive to any one of the NSAIDs may also be sensitive to any of the other NSAIDs.

Aseptic Meningitis: In occasional cases, with some NSAIDs, the symptoms of aseptic meningitis (stiff neck, severe headaches, nausea and vomiting, fever or clouding of consciousness) have been observed. Patients with autoimmune disorders (systemic lupus erythematosus, mixed connective tissue diseases, etc.) seem to be predisposed. Therefore, in such patients, the physician must be vigilant to the development of this complication.

Pregnancy, Labor and Lactation: The known effects of drugs of this class on the human fetus during the third trimester of pregnancy are closure of the ductus arteriosis, platelet dysfunction with resultant bleeding, renal dysfunction or failure with oligohydramnios, gastrointestinal bleeding or perforation and myocardial degenerative changes.

Administration of indomethacin is therefore not recommended during pregnancy or in nursing mothers.

Children: The drug should not be prescribed for children as safe conditions for use have not been established. In a few cases of severe juvenile rheumatoid arthritis, where indomethacin was given along with other drugs, severe reactions, including fatalities, were reported.

Other: Occupational Hazards: Patients should be warned that they may experience dizziness and in this event should not operate motor vehicles and should avoid potentially dangerous activities which require alertness.

Indomethacin should be used with caution in patients with psychiatric disturbances, epilepsy, or parkinsonism, since it may, in some instances, aggravate these conditions.

Precautions: Gastrointestinal: There is no definitive evidence that the concomitant administration of histamine H2-receptor antagonists and/or antacids will either prevent the occurrence of gastrointestinal side effects or allow the continuation of indomethacin therapy when and if these adverse reactions appear.

Indomethacin, both capsules and suppositories, should be used with caution because of the gastrointestinal reactions which may occur. The gastrointestinal effects may be decreased by giving the oral formulations of the drug immediately after meals, with food or with antacids. The risk of continuing therapy with indomethacin in the face of such symptoms must be weighed against the possible benefits to the individual patient. Indomethacin suppositories should be given with caution to patients with any anal or rectal pathology.

Studies in normal subjects with radioactive chromate-tagged red blood cells indicate that large doses of indomethacin (50 mg 4 times a day) produce less fecal blood loss than average doses of ASA (600 mg 4 times a day). Indomethacin however may cause single or multiple ulceration of the stomach, duodenum, or small and large intestine. There have been reports of severe bleeding and of perforation with a few fatalities. Patients may also develop gastrointestinal bleeding with no obvious ulcer formation. If gastrointestinal bleeding occurs, the drug should be discontinued. In many patients with peptic ulceration, a history of a previous ulcer was present or they were on concomitant steroids, salicylates or phenylbutazone. A possible potentiation of the ulcerogenic effect of these drugs cannot be ruled out at present. In some patients there was no history of a previous ulcer and other drugs were not being given. As a result of obvious or occult gastrointestinal bleeding some patients may manifest anemia. For this reason appropriate blood determinations are recommended periodically.

Renal Function: Long-term administration of NSAIDs to animals has resulted in renal papillary necrosis and other abnormal renal pathology. In humans, there have been reports of acute interstitial nephritis with hematuria, proteinuria, and occasionally nephrotic syndrome.

A second form of renal toxicity has been seen in patients with prerenal conditions leading to the reduction in renal blood flow or blood volume, where the renal prostaglandins have a supportive role in the maintenance of renal perfusion. In these patients, administration of a NSAID may cause a dose-dependent reduction in prostaglandin formation and may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics, and the elderly. Discontinuation of nonsteroidal anti-inflammatory therapy is usually followed by recovery to the pretreatment state.

Indomethacin and its metabolites are eliminated primarily by the kidneys; therefore, the drug should be used with great caution in patients with impaired renal function. In these cases, utilization of lower doses of indomethacin should be considered and patients carefully monitored.

During long-term therapy kidney function should be monitored periodically.

Increases in serum potassium concentration, including hyperkalemia, have been reported, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state (see Drug Interactions).

Since indomethacin is eliminated primarily by the kidneys, patients with significantly impaired renal function should be closely monitored; a lower daily dosage should be used to avoid excessive drug accumulation.

Genitourinary Tract: Some NSAIDs are known to cause persistent urinary symptoms (bladder pain, dysuria, urinary frequency), hematuria or cystitis. The onset of these symptoms may occur at any time after the initiation of therapy with an NSAID. Some cases have become severe on continued treatment. Should urinary symptoms occur, treatment with indomethacin must be stopped immediately to obtain recovery. This should be done before any urological investigations or treatments are carried out.

Hepatic Function: As with other NSAIDs, borderline elevations of one or more liver function tests may occur in up to 15% of patients. These abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy. Significant (3 times the upper limit of normal) elevations of ALT or AST occurred in controlled clinical trials in less than 1% of patients receiving therapy with NSAIDs. 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 more severe hepatic reaction while on therapy with this drug. Severe hepatic reactions including jaundice and cases of fatal hepatitis have been reported with NSAIDs.

Although such reactions are rare, if abnormal liver tests persist or worsen, if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), this drug should be discontinued.

During long-term therapy, liver function tests should be monitored periodically. If there is a need to prescribe this drug in the presence of impaired liver function, it must be done under strict observation.

Fluid and Electrolyte Balance: Fluid retention and edema have been observed in patients treated with indomethacin. Therefore, as with many other NSAIDs, the possibility of precipitating congestive heart failure in elderly patients or those with compromised cardiac function should be borne in mind. Indomethacin should be used with caution in patients with heart failure, hypertension or other conditions predisposing to fluid retention.

With nonsteroidal anti-inflammatory treatment there is a potential risk of hyperkalemia, particularly in patients with conditions such as diabetes mellitus or renal failure; elderly patients; or in patients receiving concomitant therapy with b-adrenergic blockers, angiotensin converting enzyme inhibitors or some diuretics. Serum electrolytes should be monitored periodically during long-term therapy, especially in those patients who are at risk.

Hematology: Drugs inhibiting prostaglandin biosynthesis do interfere with platelet function to varying degrees; therefore, patients who may be adversely affected by such an action should be carefully observed when indomethacin is administered.

Blood dyscrasias (such as neutropenia, leukopenia, thrombocytopenia, aplastic anemia and agranulocytosis) associated with the use of NSAIDs are rare, but could occur with severe consequences.

Indomethacin, like other NSAIDs, can inhibit platelet aggregation. This effect is of shorter duration than that seen with ASA and usually disappears within 24 hours after discontinuation of indomethacin. Indomethacin has been shown to prolong bleeding time (but within the normal range) in normal subjects. Because this effect may be exaggerated in patients with underlying hemostatic defects, indomethacin should be used with caution in persons with coagulation defects.

Infection: In common with other anti-inflammatory drugs, indomethacin may mask the usual signs of infection.

Ophthalmology: Blurred and/or diminished vision has been reported with the use of indomethacin and other NSAIDs. If such symptoms develop, this drug should be discontinued and an ophthalmologic examination performed; ophthalmic examination should be carried out at periodic intervals in any patient receiving this drug for an extended period of time.

CNS: Some patients may experience drowsiness, dizziness, vertigo, insomnia or depression with the use of indomethacin. If patients experience these side effects, they should exercise caution in carrying out activities that require alertness.

Headaches may occur, usually early in treatment with indomethacin. If headaches persist despite dosage reduction, therapy with indomethacin should be discontinued (see Warnings).

Hypersensitivity Reactions: Patients should be followed carefully to detect unusual manifestations of drug sensitivity, and since advancing years appear to increase the possibility of adverse reactions, indomethacin should be used with greater care in the elderly.

Drug Interactions: ASA or other NSAIDs: The use of indomethacin in addition to any other NSAID, including those over the counter ones (such as ASA and ibuprofen) is not recommended due to the possibility of additive side effects.

Controlled clinical studies have shown that the combined used of indomethacin and ASA does not produce any greater therapeutic effect than the use of indomethacin alone. Furthermore, in one of these clinical studies, 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 ASA/day decreases indomethacin blood levels approximately 20%.

Digoxin: Indomethacin given concomitantly with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Therefore, when indomethacin and digoxin are used concomitantly, serum digoxin levels should be closely monitored.

Anticoagulants: Numerous studies have shown that the concomitant use of NSAIDs and anticoagulants increases the risk of gastrointestinal adverse events such as ulceration and bleeding.

Because prostaglandins play an important role in hemostasis, and NSAIDs affect platelet function, concurrent therapy of indomethacin with warfarin requires close monitoring to be certain that no change in anticoagulant dosage is necessary.

Clinical studies have shown that indomethacin did not influence the hypoprothrombinemia produced by the use of anticoagulants in patients and in normal subjects. However, when any additional drug, including indomethacin is added to the treatment of patients on anticoagulant therapy, the patient should be observed closely for alterations of the prothrombin time.

Oral Hypoglycemics: Indomethacin and hypoglycemic agents should not be used concomitantly.

Diuretics: In some patients, the administration of indomethacin can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing, and thiazide diuretics. Therefore, when indomethacin and diuretics are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained.

Indomethacin 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 agents.

It has been reported that the addition of triamterene to a maintenance schedule of indomethacin resulted in reversible acute renal failure in 2 of 4 healthy volunteers. Indomethacin and triamterene should not be administered together.

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.

Most of the above effects concerning diuretics have been attributed, at least in part, to mechanisms involving inhibition of prostaglandin synthesis by indomethacin.

Antihypertensives: Coadministration of indomethacin and some antihypertensive agents has resulted in an attenuation of the latter's hypotensive effect acutely, due at least in part to indomethacin's inhibition of prostaglandin synthesis. Caution should be exercised when considering the addition of indomethacin to the regimen of a patient taking one of the following antihypertensive agents; an alpha-adrenergic blocking agent (such as prazosin), an angiotensin converting enzyme inhibitor (such as captopril or lisinopril), a beta-adrenergic blocking agent, a diuretic (see Diuretics), or hydralazine.

A decrease in the antihypertensive effect of beta-adrenergic receptor blocking agents by NSAIDs including indomethacin has been reported. Therefore, when using a beta-blocking agent to treat hypertension, patients should be observed carefully in order to confirm that the desired therapeutic effect has been obtained.

Glucocorticoids: Numerous studies have shown that the concomitant use of NSAIDs and oral glucocorticoids increases the risk of gastrointestinal side effects such as ulceration and bleeding. This is especially the case in older (>65 years of age) individuals.

Methotrexate: Caution should be used if indomethacin is administered simultaneously with methotrexate. Indomethacin has been reported to decrease the tubular secretion of methotrexate and to potentiate toxicity.

Lithium: Indomethacin 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 resulting in renal vasoconstriction and decreased lithium excretion. As a consequence, when indomethacin and lithium are given concomitantly, the patient should be carefully observed for signs of lithium toxicity. (Read the product monographs for the appropriate lithium preparation 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.

Other Drug Interactions : Cyclosporine: Administration of NSAIDs 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 monitored carefully.

Diflunisal: The combined used of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage. The coadministration of diflunisal and indomethacin results in an increase of about 30 to 35% in indomethacin plasma levels and a concomitant decrease in renal clearance of indomethacin and its conjugate. Therefore, indomethacin and diflunisal should not be used concomitantly.

Probenecid: When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased. Therefore, a lower total daily dosage of indomethacin may produce a therapeutic effect. When increases in the dose of indomethacin are made under these circumstances, they should be made cautiously and in small increments.

Phenylpropanolamine: Hypertensive crises have been reported due to oral phenylpropanolamine alone and rarely to phenylpropanolamine given with indomethacin. This additive effect is probably due at least in part to indomethacin's inhibition of prostaglandin synthesis. Caution should be exercised when indomethacin and phenylpropanolamine are administered concomitantly.

Clinical Laboratory Tests: False-negative results in the dexamethasone suppression test (DST) in patients being treated with indomethacin have been reported. Thus, results of the DST should be interpreted with caution in these patients.

Adverse Reactions: The most common adverse reactions encountered with NSAIDs are gastrointestinal, of which peptic ulcer, with or without bleeding, is the most severe. Fatalities have occurred, particularly in the elderly.

The following adverse reactions for capsules have been arranged into 2 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 (see Table I).

In controlled clinical trials, the incidence of adverse reactions to indomethacin SR capsule and equal 24-hour doses of indomethacin capsules were similar.

The adverse reactions reported with indomethacin capsules may occur with use of the suppositories. In addition, rectal irritation and tenesmus have been reported in patients who have received the suppositories.

Gastrointestinal: Incidence >1%: nausea* with or without vomiting; dyspepsia* (including indigestion, heartburn and epigastric pain); diarrhea; abdominal distress or pain; constipation.

Incidence < 1%: anorexia; bloating (includes distention); flatulence; peptic ulcer; gastroenteritis; rectal bleeding; proctitis; single and multiple ulcerations, including perforation and hemorrhage of the esophagus, stomach, duodenum or small or 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).

CNS: Incidence >1%: headache; dizziness*; vertigo; somnolence; depression and fatigue (including malaise and listlessness).

Incidence < 1%: anxiety (includes nervousness); muscle weakness; involuntary muscle movements; insomnia; muzziness; psychic disturbances including psychotic episode; mental confusion; drowsiness, lightheadedness; syncope; paresthesia; aggravation of epilepsy and parkinsonism; depersonalization; coma; peripheral neuropathy; convulsions; dysarthria.

Dermatologic: Incidence >1%: none.

Incidence <1%: pruritus; rash; urticaria; petechiae or ecchymosis; exfoliative dermatitis; erythema nodosum; loss of hair; Stevens-Johnson syndrome; erythema multiforme; toxic epidermal necrolysis.

Cardiovascular: Incidence >1%: none.

Incidence <1%: hypertension; hypotension; tachycardia; chest pain; congestive heart failure; arrhythmia; palpitations.

Special Senses: Incidence >1%: tinnitus.

Incidence <1%: 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.

Hematologic: Incidence >1%: none.

Incidence <1%: leukopenia; bone marrow depression; anemia secondary to obvious or occult gastrointestinal bleeding; aplastic anemia; hemolytic anemia; agranulocytosis; thrombocytopenic purpura; disseminated intravascular coagulation.

Genitourinary: Incidence >1%: none.

Incidence <1%: hematuria; vaginal bleeding; proteinuria; nephrotic syndrome; interstitial nephritis; BUN elevation; renal insufficiency, including renal failure.

Hypersensitivity: Incidence >1%: none.

Incidence <1%: acute anaphylaxis; acute respiratory distress; rapid fall in blood pressure resembling a shock-like state; angioedema; dyspnea; asthma; purpura; angiitis; pulmonary edema.

Metabolic: Incidence >1%: none.

Incidence <1%: edema; weight gain; fluid retention; flushing or sweating; hyperglycemia; glycosuria; hyperkalemia.

Miscellaneous: Incidence >1%: none.

Incidence <1%: epistaxis; breast changes, including enlargment and tenderness, or gynecomastia.

*Reactions occurring in 3 to 9% of patients treated with indomethacin. (Those reactions occurring in less than 3% of the patients are unmarked.)

The following local adverse reactions have been associated with the use of indomethacin suppositories: tenesmus, proctitis, rectal bleeding, burning, pain, discomfort and itching.

The following additional side effects have been reported; however a causal relationship to therapy with indomethacin has not been established.

Cardiovascular: thrombophlebitis.

Hematologic: Although there have been several reports of leukemia, the supporting information is weak.

Genitourinary: urinary frequency.

Tabulation of Frequency of Adverse Reactions Body System Frequency of Adverse Reactions

Frequent (Incidence >1%) Rare (Incidence <1%)

Gastrointestinal Nausea* with or without vomiting; dyspepsia* (including indigestion, heartburn and epigastric pain), diarrhea, abdominal distress or pain, constipation. Anorexia; bloating (including distention); flatulence; peptic ulcer; gastroenteritis; rectal bleeding; proctitis; single and multiple ulcerations, including perforation and hemorrhage of the esophagus, stomach, duodenum or small or 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).

CNS Headache; dizziness*; vertigo; somnolence; depression and fatigue (including malaise and listlessness). Anxiety (includes nervousness); muscle weakness; involuntary muscle movements; insomnia; muzziness; psychic disturbances including psychotic episode; mental confusion; drowsiness; lightheadedness; syncope; paresthesia; aggravation of epilepsy and parkinsonism; depersonalization; coma; peripheral neuropathy; convulsions; dysarthria.

Dermatologic None. Pruritus; rash; urticaria; petechiae or ecchymosis; exfoliative dermatitis; erythema nodosum; loss of hair; Stevens-Johnson syndrome; erythema multiforme; toxic epidermal necrolysis.

Cardiovascular None. Hypertension; hypotension; tachycardia; chest pain; congestive heart failure; arrhythmia; palpitations.

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.

Hematologic None. Leukopenia; bone marrow depression; anemia secondary to obvious or occult gastrointestinal bleeding; aplastic anemia; hemolytic anemia; agranulocytosis; thrombocytopenic purpura; disseminated intravascular coagulation.

Genitourinary None. Hematuria; vaginal bleeding; proteinuria; nephrotic syndrome; interstitial nephritis; BUN elevation; renal insufficiency, including renal failure.

Hypersensitivity None. Acute anaphylaxis; acute respiratory distress; rapid fall in blood pressure resembling a shock-like state; angioedema; dyspnea; asthma; purpura; angiitis; pulmonary edema.

Metabolic None. Edema; weight gain; fluid retention; flushing or sweating; hyperglycemia; glycosuria; hyperkalemia.

Miscellaneous None. Epistaxis; breast changes, including enlargement and tenderness or gynecomastia.

*Reactions occurring in 3 to 9% of patients treated with indomethacin. (Those reactions occurring in less than 3% of the patients are unmarked.)

Symptoms And Treatment Of Overdose: Symptoms: Relatively little experience is available recording overdosage with indomethacin. Nausea, vomiting, intense headache, dizziness, mental confusion, disorientation, or lethargy may be observed. There have been reports of paresthesia, numbness, and convulsions. Signs of gastrointestinal hemorrhage could appear but have not been reported following the acute ingestion of large amounts of indomethacin accidentally or intentionally. tag_Treatment

Treatment: Symptomatic and supportive treatment include emptying the stomach as quickly as possible by emesis or lavage 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.

Dosage And Administration: In chronic disorders, treatment should be started with a dosage of 25 mg 2 or 3 times a day. By starting therapy with low dosage, increased gradually when necessary, maximum benefit will be produced with fewer adverse reactions.

Always give indomethacin with food, immediately after meals, or with antacids to reduce gastric irritation.

As with all drugs, the lowest possible effective dose should be utilized for each individual patient.

Children: The drug should not be prescribed for children because safe conditions for use have not been established.

Geriatrics: Since advancing years appear to increase the possibility of adverse reactions, indomethacin should be used with greater care in the elderly.

Adult Dosage Recommendations: Rheumatoid Arthritis and Ankylosing (Rheumatoid) Spondylitis: Initial Dosage: 25 mg 2 or 3 times a day. If the response is not adequate, increase the daily dosage by 25 mg at about weekly intervals until a satisfactory response is obtained or a dosage of 150 to 200 mg/day is reached. If a satisfactory response is not obtained with 200 mg a day, larger doses probably will not be effective.

If adverse reactions develop as the dosage is increased, reduce the dosage to a tolerated level and maintain this for 3 to 4 weeks. If an adequate response has not been obtained, gradually increase the daily dosage by 25 mg at about weekly intervals to 150 to 200 mg daily.

For patients with acute rheumatoid arthritis or with acute flares of chronic rheumatoid arthritis, increase the dosage daily by 25 mg until a satisfactory response is obtained or a total daily dosage of 150 to 200 mg is reached. If adverse effects develop as the dosage is increased, the dosage should be reduced to a tolerated level for 2 or 3 days, and then, gradually increased by 25 mg every few days as tolerated. After the acute phase is under control, it is often possible to reduce the daily dosage gradually to 75 to 100 mg.

Reduction of Steroid Dosage: Use of indomethacin often will permit a gradual reduction of steroid dosage by 25 to 50%. In some patients, steroids can be slowly discontinued over a period of several weeks or months. The usual precautions should be observed in withdrawing steroids.

Severe Osteoarthritis and Degenerative Joint Disease of the Hip: Initial dosage: 25 mg 2 or 3 times a day. If the response is not adequate, increase the daily dosage by 25 mg at about weekly intervals until a satisfactory response is obtained or a dosage of 150 to 200 mg a day is reached. If a satisfactory response is not obtained with 200 mg a day, larger doses will probably not be effective.

If adverse reactions develop as the dosage is increased, reduce the dosage to a tolerated level and maintain this for 3 to 4 weeks. If an adequate response has not then been obtained, gradually increase the daily dosage by 25 mg at about weekly intervals to 150 to 200 mg daily.

Gout: To control acute attacks: 50 mg 3 times a day until all signs and symptoms subside. 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.

Use of Alternate Dosage Forms: Suppositories: The recommended dosage is 100 to 200 mg daily and should be individually adjusted to the patient's response and tolerance. Daily dose of 100 mg can be given as 50 mg twice daily or as 100 mg at night. Doses higher than 100 mg must be given on a twice daily schedule.

Combined administration: One 50 mg or 100 mg suppository at bedtime, supplemented the following day by 25 mg capsules as needed up to a total of 150 mg to 200 mg of indomethacin. The total daily dose of indomethacin (capsules and suppositories) should not exceed 200 mg.

Children: Indomethacin should not be prescribed for children because safe conditions for use have not been established (see Warnings).



Availability And Storage: Capsules: 25 mg: Each opaque blue and white capsule imprinted with INDOTEC 25 and "TEC" contains: indomethacin 25 mg. Nonmedicinal ingredients: black iron oxide, colloidal silicon dioxide, D&C yellow #10 aluminum lake, FD&C blue #1 aluminum lake, FD&C blue #2 aluminum lake, FD&C red #3, FD&C red #40 aluminum lake, gelatin, lactose, magnesium stearate, microcrystalline cellulose, pregelatinized cornstarch, shellac, silicon dioxide, sodium lauryl sulfate and titanium dioxide. Gluten- and tartrazine-free. Bottles of 100, 500 and 1 000. Store between 15 and 30°C. Protect from light and moisture. Store in a tight container.

50 mg: Each opaque blue and white capsule, imprinted with INDOTEC 50 and "TEC" contains: indomethacin 50 mg. Nonmedicinal ingredients: black iron oxide, colloidal silicon dioxide, D&C yellow #10 aluminum lake, FD&C blue #1 aluminum lake, FD&C blue #2 aluminum lake, FD&C red #3, FD&C red #40 aluminum lake, gelatin, lactose, magnesium stearate, microcrystalline cellulose, pregelatinized cornstarch, shellac, silicon dioxide, sodium lauryl sulfate and titanium dioxide. Gluten- and tartrazine-free. Bottles of 100 and 500. Store between 15 and 30°C. Protect from light and moisture. Store in a tight container.

Suppositories: 50 mg: Each torpedo-shaped, smooth surface, yellowish-white suppository contains: indomethacin 50 mg. Nonmedicinal ingredients: butylated hydroxyanisole, butylated hydroxytoluene, EDTA, glycerin, polyethylene glycol and sodium chloride. Boxes of 30. Store below 30°C. Protect from light and elevated humidity. Keep away from excessive heat. Preserve in well-closed containers, at controlled room temperature.

100 mg: Each torpedo-shaped, smooth surface, yellowish-white suppository contains: indomethacin 100 mg. Nonmedicinal ingredients: butylated hydroxyanisole, butylated hydroxytoluene, EDTA, glycerin, polyethylene glycol and sodium chloride. Boxes of 30. Store below 30°C. Protect from light and elevated humidity. Keep away from excessive heat. Preserve in well-closed containers, at controlled room temperature.