Indomethacin

Feverfew: In theory, concomitant use of feverfew and indomethacin may predispose patients to more adverse effects of nonsteroidal anti-inflammatory agents (e.g., gastropathy, renal dysfunction and increased risk of bleeding). Concurrent use should be avoided. Probable mechanism is additive prostaglandin and thromboxane inhibition.

Garlic: Caution is advised with the concomitant use of indomethacin and garlic because of the increased risk of bleeding. The probable mechanism involves potentiation of antiplatelet aggregation.

Ginkgo: Avoid the concomitant use of indomethacin and ginkgo because of the increased risk of bleeding. The probable mechanism is potentiation of antiplatelet aggregation. If both agents must be used together monitor bleeding time and signs and symptoms of bleeding.

Use caution with concomitant use of indomethacin and other natural health products with anticoagulant or antiplatelet properties.

Nonsteroidal anti-inflammatory drugs may cause gastrointestinal bleeding, which may produce positive fecal hemoccult test results in some individuals and therefore interfere with screening for colorectal cancer. When screening for occult fecal blood loss, nonsteroidal anti-inflammatory drugs may need to be withheld for 2 to 4 days prior to testing, as a positive fecal hemoccult test may be attributable to nonsteroidal anti-inflammatory drug therapy.

Indomethacin decreases platelet aggregation and prolongs bleeding time. The effect of indomethacin on bleeding time should be taken into account when the test is performed.

Indomethacin may cause a false negative dexamethasone suppression test in patients with depression.

Because indomethacin is a nonsteroidal anti-inflammatory drug most of the potentially serious drug interactions are related to increasing the risks of serious gastrointestinal adverse effects, hyperkalemia, renal dysfunction and coagulopathies. Most of the drug interactions are potentially pharmacodynamic in nature, rather than pharmacokinetic. (See Table 2.)

Indomethacin is a strong inhibitor as well as a substrate of CYP 2C9; there is a theoretical potential for interaction with other drugs significantly metabolized by this enzyme.

The initial dose should be one-half the usual adult dose. The maintenance dose should be reduced by 25% in elderly patients because pharmacokinetic studies indicate decreased clearance and increased half-life in such patients.

Indomethacin capsules should be swallowed whole, not crushed or chewed. Indomethacin should be administered with food or meals.

Patients should be instructed to take a missed dose as soon as they remember, and not to double the dose or exceed their daily recommended dose.

Indomethacin should be avoided in patients with significant hepatic impairment.

Use the lowest effective dose, for the shortest duration necessary to control symptoms.

No dosage adjustment is required for patients with renal dysfunction or failure. While there is not a significant prolongation of the drug's half-life, as with any NSAID, indomethacin should be used with caution in patients with renal dysfunction.

Dosage supplementation is not necessary following hemodialysis, continuous ambulatory peritoneal dialysis or continuous arteriovenous hemodialysis.

Moderate to severe rheumatoid arthritis, including acute flares of chronic disease

Based on pharmacokinetic data, the total amount of drug absorbed from the rectal suppository is expected to be similar to that from the capsule. Clinical trials suggest the amount of indomethacin absorbed from the suppository is between 80 and 90%. It is suggested that the total daily dose of indomethacin administered rectally not exceed 200 mg. In patients who have persistent night pain or morning stiffness, up to 100 mg of the total daily dose may be given at bedtime either orally or rectally to help with symptoms.

Proteinuria and nephrotic syndrome have been reported.

Hepatitis, jaundice and liver function test abnormalities have been reported.

Some NSAIDs are associated with persistent urinary symptoms (bladder pain, dysuria, urinary frequency), hematuria, interstitial nephritis or cystitis. The initiation of these symptoms may occur at any time after the initiation of therapy with a nonsteroidal anti-inflammatory drug. Should urinary symptoms occur, in the absence of an alternative explanation, stop treatment with indomethacin to ascertain if symptoms disappear. This should be done before urological investigations or treatments are considered.

Peptic ulcer, gastrointestinal bleeding and perforation, anorexia and gastritis.

Acute anaphylaxis, acute respiratory distress, angioedema and fever have been reported in patients using NSAIDs.

Leukopenia, coagulopathy, and rarely aplastic anemia have reported with the use of indomethacin, especially following chronic ingestion with therapeutic doses. Bone marrow suppression, agranulocytosis and hemolytic anemia have also been reported. Indomethacin as a nonsteroidal anti-inflammatory drug can inhibit platelet aggregation within 2 hours of taking the drug. The mechanism of this response is related to the inhibition of prostaglandin synthetase.

Indomethacin may cause drowsiness. Therefore patients should be cautioned against engaging in activities requiring mental alertness and motor coordination such as driving or operating machinery.

There have been rare reports of peripheral neuropathy; symptoms disappeared when the drug was discontinued. Pseudotumor cerebri and seizures have been reported rarely with indomethacin use.

Anxiety, fatigue, paresthesia, insomnia, psychotic disturbances, mental confusion, light-headedness, syncope, peripheral neuropathy and seizures have all been reported.

Isolated cases of male sexual dysfunction have been reported.

Edema, hyperkalemia and hypo/hyperglycemia, blurred vision, retinal/macular disturbances. Aseptic meningitis has been reported rarely with NSAID use.

Rarely, rash, urticaria, pruritus, alopecia, Stevens-Johnson syndrome, toxic epidermal necrolysis, purpura, psoriasis and petechiae have been reported with NSAID use.

Hypertension, hypotension and heart failure have been reported.

Use with caution in geriatric individuals 65 years or older since increasing age may be associated with increased risk of adverse events. See Warnings and Precautions.

Indomethacin ordinarily should not be prescribed for children 14 years of age and under. See Warnings and Precautions. However, intravenous indomethacin has been used to facilitate closure of a patent ductus arteriosus in premature infants.

Acute renal failure which is usually reversible has been reported with the use of indomethacin. In many cases onset of renal failure occurs within 2 days to 2 weeks of initiating therapy. Renal failure has occurred in the absence of pre-existing impairment. Patients at greatest risk are those with renal and hepatic impairment, heart failure, diabetes mellitus, hypovolemia, advanced age, concurrent use of other nephrotoxic drugs or pyelonephritis. Renal dysfunction with indomethacin is likely related to inhibition of prostaglandin synthesis and renin-induced vasoconstriction.

As with other NSAIDs, indomethacin has been associated with hyperkalemia (see Fluid and Electrolyte Balance).

Gastrointestinal toxicity and symptoms are possible with both the oral and rectal use of indomethacin.

Serious gastrointestinal toxicity, such as ulceration, perforation, obstruction and gastrointestinal bleeding, sometimes severe and potentially fatal, can occur at any time, with or without symptoms in patients treated with NSAIDs, including indomethacin.

Gastrointestinal symptoms such as dyspepsia are common, usually developing early in therapy. Dyspepsia does not necessarily correlate with mucosal damage. Health care providers should remain alert for ulceration and bleeding in patients treated with NSAIDs, even in the absence of gastrointestinal symptoms.

In patients observed in clinical trials of such drugs, 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. The incidence of these complications is related to dose, past history of known ulcer disease, concurrent use of more than one NSAID and advanced age (see Special Populations).

Indomethacin should be given under close medical supervision to patients with a history of ulcer of the upper gastrointestinal tract or inflammatory disease of the gastrointestinal tract such as ulcerative colitis or Crohn's disease. In these cases the health care provider must weigh the benefits of treatment against the potential adverse effects.

Patients should be informed of the signs and symptoms of serious toxicity and instructed to contact a health care provider immediately if they experience persistent dyspepsia or other signs or symptoms suggestive of gastrointestinal bleeding or ulceration. If ulceration is suspected or confirmed, or if gastrointestinal bleeding occurs, discontinue indomethacin immediately, institute appropriate therapy and monitor the patient closely.

Because serious gastrointestinal tract ulceration and bleeding can occur without warning symptoms, health care providers should follow chronically treated patients and watch for signs and symptoms of ulceration and bleeding and should inform patients of the importance of this follow-up.

The major risk factors are a prior history of serious gastrointestinal events and advancing age. Other possible risk factors include H. pylori infection, excessive ethanol intake, smoking, concurrent use of more than one NSAID, high doses of NSAID, and concomitant use of oral corticosteroids, anticoagulants, antiplatelet agents (including ASA) or selective serotonin reuptake inhibitors (SSRIs). Consider concomitant cytoprotective therapy (using a proton pump inhibitor, misoprostol or twice the standard dose of an H₂ receptor antagonist such as famotidine or ranitidine) in patients with one or more risk factors for serious gastrointestinal events.

Indomethacin should not be used in children under the age of two years except as intravenous indomethacin to facilitate closure of a patent ductus arteriosus in premature infants (see Indocid P.D.A. monograph). Effectiveness of indomethacin in children has not been established. Indomethacin should not be prescribed for children 14 years of age and younger unless toxicity or lack of efficacy associated with other drugs warrants the risk. The lowest effective dose should be used. Limited clinical information suggests the adverse effects experienced by children receiving indomethacin are similar to those in adults. Fatal hepatitis has been reported in children with juvenile rheumatoid arthritis treated with indomethacin. Experience with indomethacin in children >2 years of age is limited to the capsule formulation.

ASA-induced asthma is an uncommon but very important indication of ASA and NSAID sensitivity. It occurs more frequently in patients with asthma who have nasal polyps.

Blurred and/or diminished vision have been reported with the use of NSAIDs and may be early symptoms of adverse ocular effects of indomethacin. Corneal deposits and retinal disturbances have been reported in patients receiving chronic indomethacin therapy. Blurred vision warrants evaluation by an ophthalmologist. Generally the symptoms are reversible when indomethacin is stopped. If long-term therapy with indomethacin is warranted, consider routine evaluation by an ophthalmologist since some patients will have no symptoms.

As with all NSAIDs, the use of indomethacin in pregnancy should be weighed against the risks and should not be used unless considered essential. The drug is generally considered safe for short periods of time in the second trimester of pregnancy. Long term use (>48 hours) and third trimester use are contraindicated.

A relationship between indomethacin and the development of psychosis, aggressive behavior and cognitive dysfunction is especially evident in patients of advanced age. Patients do not necessarily have a history of previous psychiatric disturbances or cognitive impairment. Withdrawal of the drug and appropriate therapy usually reverses these symptoms.

Ototoxicity including tinnitus and hearing loss has been reported with all nonsteroidal anti-inflammatory drugs. The incidence of ototoxicity appears to be greater for ASA compared to indomethacin.

Elderly, frail or debilitated patients are most susceptible to the adverse effects associated with nonsteroidal anti-inflammatory drugs; the incidence of these adverse effects increases with the dose and duration of treatment. In addition these patients are at increased risk of lower esophageal ulceration and bleeding. Most reports of fatal gastrointestinal events are in this population, especially those with pre-existing cardiovascular disease.

As with other NSAIDs, borderline elevations of one or more liver enzyme tests (AST, ALT, ALP) may occur in up to 15% of patients. These abnormalities may progress, remain unchanged, and/or be transient with continued therapy.

Fatal hepatitis has been reported in children with juvenile rheumatoid arthritis treated with indomethacin.

Patients with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred should be evaluated for evidence of a more serious hepatic reaction while on therapy with indomethacin. Severe hepatic reactions including jaundice and cases of fatal hepatitis have been reported with nonsteroidal 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 (e.g., jaundice) or if systemic manifestations occur (e.g., eosinophilia, rash) indomethacin should be discontinued. In the presence of liver disease, indomethacin should be used with extreme caution.

In patients with coagulopathies, in those receiving anticoagulants and in those at risk for blood dyscrasias indomethacin should be used with caution because hematologic side effects may be more likely to occur. See Adverse Reactions, Hematologic.

Cross-sensitivity: Patients sensitive to any nonsteroidal anti-inflammatory drugs, including acetylsalicylic acid may be sensitive to indomethacin. ASA-intolerance: As with nonsteroidal anti-inflammatory drugs in general, some patients may experience urticaria upon exposure to indomethacin. Patients with partial or complete syndrome of ASA-intolerance should not be given indomethacin (see Contraindications).

The lowest possible effective dose for the individual patient should be prescribed, for the shortest possible duration. Increasing the dose, particularly over 200 mg per day, increases the risk of adverse effects, without corresponding increase in clinical benefits.

Aseptic Meningitis: In occasional cases, with some nonsteroidal anti-inflammatory drugs, the symptoms of aseptic meningitis (stiff neck, severe headache, nausea and vomiting, fever or clouding of consciousness) have been observed. Patients with autoimmune disorders (e.g., systemic lupus erythematosus, mixed connective tissue diseases) seem to be predisposed. Health care providers must be vigilant in monitoring for this potential adverse effect.

Infection: In common with other NSAIDs, indomethacin may suppress fever.

As with other NSAIDs, indomethacin is a reversible inhibitor of platelet aggregation. The drug should be discontinued 4 to 7 days before surgery to reduce the risk of bleeding. Consider discontinuing indomethacin 2 weeks before surgery where bleeding could be catastrophic, such as with neurosurgery. Indomethacin is contraindicated in the perioperative treatment of pain in coronary artery bypass graft (CABG) surgery (see Contraindications).

With chronic use of indomethacin, consider obtaining a baseline hemoglobin, serum creatinine, serum potassium and sodium, complete blood count, fecal occult blood test and liver function tests before or within a month of initiating therapy. Repeat these tests periodically during therapy or if toxicities are suspected. High-risk (e.g., older than 65 years; pediatric patients; history of peptic ulcer disease; prolonged use of high-dose indomethacin; concurrent use of potentially nephrotoxic drugs, corticosteroids, antiplatelets, anticoagulants or drugs affecting serum potassium) may require monitoring every 3 months. If long-term therapy with indomethacin is warranted, consider routine evaluation by an ophthalmologist.

Counsel patients to inform their health care providers immediately of symptoms of serious adverse events associated with indomethacin therapy such as gastrointestinal ulceration and bleeding, changes in vision, symptoms of heart or renal failure, bruising and nongastrointestinal bleeding, hypersensitivity and severe headache.

Patients sensitive to any one of the NSAIDs may be sensitive to any of the other drugs of this class.

Serious skin reactions (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis, erythema multiforme) have been associated with the use of some NSAIDs; however, causality is not clear. Patients who experience a skin rash while on indomethacin should be advised to contact their physician for assessment and advice, as these reactions are potentially life threatening but may be reversible if the causative agent is discontinued and appropriate treatment instituted.

Fluid retention and edema have been observed in patients treated with indomethacin. Therefore the possibility of precipitating 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. Patients who are at risk for fluid retention should weigh themselves at regular intervals to assist in monitoring for fluid accumulation. With indomethacin use there is the potential risk for hyperkalemia, particularly in patients with diabetes mellitus or renal dysfunction or in patients receiving concomitant therapy with potassium supplements, angiotensin-II receptor antagonists, beta-blockers, angiotensin-converting enzyme inhibitors or potassium-sparing diuretics. It is essential that patients at risk be monitored on a routine basis for hyperkalemia. Hyponatremia has also been reported in elderly patients.

Indomethacin is excreted in breast milk likely in very small amounts. It is considered compatible with breast-feeding.

Use of indomethacin has been associated with an increased risk of serious cardiovascular adverse effects (myocardial infarction, stroke, thrombotic events). Patients with pre-existing cardiovascular disease or cardiovascular risk factors and those with a longer duration of therapy may be at higher risk. Use caution when prescribing indomethacin to patients with ischemic heart disease, cerebrovascular disease and/or heart failure, as well as to patients with risk factors for cardiovascular, cerebrovascular or renal disease (e.g., hypertension, dyslipidemias, diabetes, heart failure (NYHA I), coronary or peripheral artery disease, transient ischemic attacks, smoking, ClCr <60 mL/min).

The use of indomethacin can promote sodium retention which may exacerbate hypertension and/or heart failure. Some patients with pre-existing hypertension may develop worsening of blood pressure control when placed on indomethacin, and regular monitoring of blood pressure is essential.

At therapeutic plasma concentrations, about 99% of indomethacin is bound to plasma protein. The drug crosses the blood-brain barrier and the placenta, and is excreted in breast milk. Indomethacin and its conjugates undergo enterohepatic circulation.

Indomethacin is readily absorbed orally. Peak plasma concentrations of about 1 and 2 µg/mL are attained about 2 hours following single doses of 25 mg or 50 mg. After 4 hours, 99% of an orally administered dose has been absorbed.

Indomethacin is a nonsteroidal anti-inflammatory drug with analgesic and antipyretic properties, but exhibits these effects without altering the course of the underlying disease. It is a reversible inhibitor of the enzymes cyclooxygenase-1 and 2, thus decreasing the formation of prostaglandin precursors. This inhibition occurs in vitro and, in the concentrations reached during therapy, also has an in vivo effect.

Indomethacin is eliminated via renal and biliary excretion; about 60% of an oral dose is recovered in the urine (as drug and metabolites) and 33% in the feces. Its mean half-life is estimated to be about 4.5 hours. With doses of 25 or 50 mg TID, steady state drug plasma concentrations are on average about 1.4 times those following the first dose.

Indomethacin is metabolized in the liver and exists in the plasma as the parent drug as well as the unconjugated forms of the desmethyl, desbenzoyl and desmethyl-desbenzoyl metabolites.