Because of the variability of the potential of INDOCIN to cause adverse reactions in the individual patient, the following are strongly recommended:
The lowest possible effective dose for the individual patient should be prescribed. Increased dosage tends to increase adverse effects, particularly in doses over 150-200 mg/day, without corresponding increase in clinical benefits.
Careful instructions to, and observations of, the individual patient are essential to the prevention of serious adverse reactions. As advancing years appear to increase the possibility of adverse reactions, INDOCIN should be used with greater care in the elderly.
Effectiveness of INDOCIN in pediatric patients has not been established. INDOCIN should not be prescribed for pediatric patients 14 years of age and younger unless toxicity or lack of efficacy associated with other drugs warrants the risk.
In experience with more than 900 pediatric patients reported in the literature or to the manufacturer who were treated with 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 2 mg/kg/day given in divided doses. Maximum daily dosage should not exceed 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.
Single or multiple ulcerations, including perforation and hemorrhage of the esophagus, stomach, duodenum or small and large intestine, have been reported to occur with INDOCIN. Fatalities have been reported in some instances. Rarely, 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.
Because of the occurrence, and at times severity, of gastrointestinal reactions to INDOCIN, the prescribing physician must be continuously alert for any sign or symptom signaling a possible gastrointestinal reaction. The risks of continuing therapy with INDOCIN in the face of such symptoms must be weighed against the possible benefits to the individual patient.
INDOCIN should not be given to patients with active gastrointestinal lesions or with a history of recurrent gastrointestinal lesions except under circumstances which warrant the very high risk and where patients can be monitored very closely.
The gastrointestinal effects may be reduced by giving Capsules INDOCIN immediately after meals, with food, or with antacids.
Risk of GI Ulcerations, Bleeding and Perforation with NSAID Therapy
Serious gastrointestinal toxicity such as bleeding, ulceration, and perforation, can occur at any time, with or without warning symptoms, in patients treated chronically with NSAID therapy. Although 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 chronically with NSAIDs even in the absence of previous GI tract symptoms. In patients observed in clinical trials of several months to two years duration, symptomatic upper GI ulcers, gross bleeding or perforation appear to occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. Physicians should inform patients about the signs and/or symptoms of serious GI toxicity and what steps to take if they occur.
Studies to date have not identified any subset of patients not at risk of developing peptic ulceration and bleeding. Except for a prior history of serious GI events and other risk factors known to be associated with peptic ulcer disease, such as alcoholism, smoking, etc., no risk factors (e.g., age, sex) have been associated with increased risk. Elderly or debilitated patients seem to tolerate ulceration or bleeding less well than other individuals and most spontaneous reports of fatal GI events are in this population. Studies to date are inconclusive concerning the relative risk of various NSAIDs in causing such reactions. High doses of any NSAID probably carry a greater risk of these reactions, although controlled clinical trials showing this do not exist in most cases. In considering the use of relatively large doses (within the recommended dosage range), sufficient benefit should be anticipated to offset the potential increased risk of GI toxicity.
As with other non-steroidal anti-inflammatory drugs, long term administration of indomethacin 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 and renal conditions leading to a 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 an 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 conditions such as renal or hepatic dysfunction, diabetes mellitus, advanced age, extracellular volume depletion from any cause, congestive heart failure, septicemia, pyelonephritis, or concomitant use of any nephrotoxic drug. INDOCIN or other NSAIDs should be given with caution and renal function should be monitored in any patient who may have reduced renal reserve. Discontinuation of NSAID therapy is typically followed by recovery to the pretreatment state.
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 PRECAUTIONS, Drug Interactions).
Since INDOCIN is eliminated primarily by the kidneys, patients with significantly impaired renal function should be closely monitored; a lower daily dosage should be anticipated to avoid excessive drug accumulation.
Corneal deposits and retinal disturbances, including those of the macula, have been observed in some patients who had received prolonged therapy with INDOCIN. The prescribing physician should be alert to the possible association between the changes noted and INDOCIN. It is advisable to discontinue therapy if such changes are observed. Blurred vision may be a significant symptom and warrants a thorough ophthalmological examination. Since these changes may be asymptomatic, ophthalmologic examination at periodic intervals is desirable in patients where therapy is prolonged.
Central Nervous System Effects:
INDOCIN may aggravate depression or other psychiatric disturbances, epilepsy, and parkinsonism, and should be used with considerable caution in patients with these conditions. If severe CNS adverse reactions develop, INDOCIN should be discontinued.
INDOCIN may cause drowsiness; therefore, patients should be cautioned about engaging in activities requiring mental alertness and motor coordination, such as driving a car. INDOCIN may also cause headache. Headache which persists despite dosage reduction requires cessation of therapy with INDOCIN.
Use in Pregnancy and the Neonatal Period
INDOCIN is not recommended for use in pregnant women, since safety for use has not been established. 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.
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.
As with other non-steroidal anti-inflammatory agents which inhibit prostaglandin synthesis, indomethacin has been found to delay parturition in rats.
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.
Use in Nursing Mothers
INDOCIN is excreted in the milk of lactating mothers. INDOCIN is not recommended for use in nursing mothers.
Non-steroidal anti-inflammatory drugs, including INDOCIN, may mask the usual signs and symptoms of infection. Therefore, the physician must be continually on the alert for this and should use the drug with extra care in the presence of existing infection.
Fluid retention and peripheral edema have been observed in some patients taking INDOCIN. Therefore, as with other non-steroidal anti-inflammatory drugs, INDOCIN should be used with caution in patients with cardiac dysfunction, hypertension, or other conditions predisposing to fluid retention.
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.
INDOCIN, like other non-steroidal anti-inflammatory agents, can inhibit platelet aggregation. This effect is of shorter duration than that seen with aspirin and usually disappears within 24 hours after discontinuation of INDOCIN. INDOCIN 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, INDOCIN should be used with caution in persons with coagulation defects.
As with other non-steroidal anti-inflammatory drugs, borderline elevations of one or more liver tests may occur in up to 15% of patients. These abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy. The SGPT (ALT) test is probably the most sensitive indicator of liver dysfunction. Meaningful (3 times the upper limit of normal) elevations of SGPT or SGOT (AST) occurred in controlled clinical trials in less than 1% of patients. 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 INDOCIN. Severe hepatic reactions, including jaundice and cases of fatal hepatitis, have been reported with INDOCIN as with other non-steroidal anti-inflammatory drugs. 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.), INDOCIN should be discontinued.
Information for Patients
INDOCIN, like other drugs of its class, is not free of side effects. The side effects of these drugs can cause discomfort and, rarely, there are more serious side effects such as gastrointestinal bleeding, which may result in hospitalization and even fatal outcomes.
NSAIDs (Non-steroidal Anti-inflammatory Drugs) are often essential agents in the management of arthritis; but they also may be commonly employed for conditions which are less serious.
Physicians may wish to discuss with their patients the potential risks (see WARNINGS, PRECAUTIONS
and ADVERSE REACTIONS) and likely benefits of NSAID treatment, particularly when the drugs are used for less serious conditions where treatment without NSAIDs may represent an acceptable alternative to both the patient and physician.
Because serious GI tract ulceration and bleeding can occur without warning symptoms, physicians should follow chronically treated patients for the signs and symptoms of ulceration and bleeding and should inform them of the importance of this follow-up (see WARNINGS, Risk of GI Ulcerations, Bleeding and Perforation with NSAID Therapy).
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.
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.
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.
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%.
The concomitant use of INDOCIN with other NSAIDs is not recommended due to the increased possibility of gastrointestinal toxicity, with little or no increase in efficacy.
Clinical studies have shown that INDOCIN does not influence the hypoprothrombinemia produced by anticoagulants. However, when any additional drug, including INDOCIN, is added to the treatment of patients on anticoagulant therapy, the patients should be observed for alterations of the prothrombin time.
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.
Caution should be used if INDOCIN is administered simultaneously with methotrexate. INDOCIN has been reported to decrease the tubular secretion of methotrexate and to potentiate its toxicity.
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 monitored.
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 INDOCIN 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.
INDOCIN given concomitantly with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Therefore, when INDOCIN and digoxin are used concomitantly, serum digoxin levels should be closely monitored.
In some patients, the administration of INDOCIN can reduce the diuretic, natriuretic, and, antihypertensive effects of loop, potassium-sparing, and thiazide diuretics. Therefore, when INDOCIN and diuretics are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained.
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.
Most of the above effects concerning diuretics have been attributed, at least in part, to mechanisms involving inhibition of prostaglandin synthesis by INDOCIN.
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. INDOCIN can reduce the antihypertensive effects of captopril and losartan.
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.
Effectiveness in pediatric patients 14 years of age and younger has not been established (see WARNINGS).
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, General ; 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, Risk of GI Ulcerations, Bleeding and Perforation with NSAID Therapy).
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).