Indocin Information
Indocin (Indomethacin) Description
Suspension Indocin (Indomethacin) for oral use contains 25 mg of indomethacin per 5 mL, alcohol 1%, and sorbic acid 0.1% added as a preservative and the following inactive ingredients: antifoam AF emulsion, flavors, purified water, sodium hydroxide or hydrochloric acid to adjust pH, sorbitol solution, and tragacanth. Indomethacin is a non-steroidal anti-inflammatory indole derivative designated chemically as 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1-indole-3-acetic acid. Indomethacin is practically insoluble in water and sparingly soluble in alcohol. It has a pKa of 4.5 and is stable in neutral or slightly acidic media and decomposes in strong alkali. The suspension has a pH of 4.0-5.0. The structural formula is:
Indocin (Indomethacin) Clinical Pharmacology
Indocin (Indomethacin) is a non-steroidal anti-inflammatory drug (NSAID) that exhibits antipyretic and analgesic properties. Its mode of action, like that of other anti-inflammatory drugs, is not known. However, its therapeutic action is not due to pituitary-adrenal stimulation.
Indocin (Indomethacin) is a potent inhibitor of prostaglandin synthesis . Concentrations are reached during therapy which have been demonstrated to have an effect as well. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Moreover, prostaglandins are known to be among the mediators of inflammation. Since indomethacin is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues.
Indocin (Indomethacin) has been shown to be an effective anti-inflammatory agent, appropriate for long-term use in rheumatoid arthritis, ankylosing spondylitis, and osteoarthritis.
Indocin (Indomethacin) affords relief of symptoms; it does not alter the progressive course of the underlying disease.
Indocin (Indomethacin) suppresses inflammation in rheumatoid arthritis as demonstrated by relief of pain, and reduction of fever, swelling and tenderness. Improvement in patients treated with Indocin (Indomethacin) for rheumatoid arthritis has been demonstrated by a reduction in joint swelling, average number of joints involved, and morning stiffness; by increased mobility as demonstrated by a decrease in walking time; and by improved functional capability as demonstrated by an increase in grip strength. Indocin (Indomethacin) may enable the reduction of steroid dosage in patients receiving steroids for the more severe forms of rheumatoid arthritis. In such instances the steroid dosage should be reduced slowly and the patients followed very closely for any possible adverse effects.
Indomethacin has been reported to diminish basal and CO stimulated cerebral blood flow in healthy volunteers following acute oral and intravenous administration. In one study after one week of treatment with orally administered indomethacin, this effect on basal cerebral blood flow had disappeared. The clinical significance of this effect has not been established.
Capsules Indocin (Indomethacin) have been found effective in relieving the pain, reducing the fever, swelling, redness, and tenderness of acute gouty arthritis (see ).
Following single oral doses of Capsules Indocin (Indomethacin) 25 mg or 50 mg, indomethacin is readily absorbed, attaining peak plasma concentrations of about 1 and 2 mcg/mL, respectively, at about 2 hours. Orally administered Capsules Indocin (Indomethacin) are virtually 100% bioavailable, with 90% of the dose absorbed within 4 hours. A single 50 mg dose of Oral Suspension Indocin (Indomethacin) was found to be bioequivalent to a 50 mg Indocin (Indomethacin) capsule when each was administered with food.
Indomethacin is eliminated via renal excretion, metabolism, and biliary excretion. Indomethacin undergoes appreciable enterohepatic circulation. The mean half-life of indomethacin is estimated to be about 4.5 hours. With a typical therapeutic regimen of 25 or 50 mg t.i.d., the steady-state plasma concentrations of indomethacin are an average 1.4 times those following the first dose.
Indomethacin exists in the plasma as the parent drug and its desmethyl, desbenzoyl, and desmethyldesbenzoyl metabolites, all in the unconjugated form. About 60 percent of an oral dosage is recovered in urine as drug and metabolites (26 percent as indomethacin and its glucuronide), and 33 percent is recovered in feces (1.5 percent as indomethacin).
About 99% of indomethacin is bound to protein in plasma over the expected range of therapeutic plasma concentrations. Indomethacin has been found to cross the blood-brain barrier and the placenta.
Indocin (Indomethacin) Indications And Usage
Carefully consider the potential benefits and risks of Indocin (Indomethacin) and other treatment options before deciding to use Indocin (Indomethacin) . Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see ).
Indomethacin has been found effective in active stages of the following:
Indocin (Indomethacin) Contraindications
Indocin (Indomethacin) is contraindicated in patients with known hypersensitivity to indomethacin or the excipients (see ).
Indocin (Indomethacin) should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic/anaphylactoid reactions to NSAIDs have been reported in such patients (see , and ).
Indocin (Indomethacin) is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see ).
Indocin (Indomethacin) Warnings
Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate over renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, patients with volume depletion, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.
Increases in serum potassium concentration, including hyperkalemia, have been reported with use of Indocin (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 ).
Indocin (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, Indocin (Indomethacin) should be discontinued.
Indocin (Indomethacin) may cause drowsiness; therefore, patients should be cautioned about engaging in activities requiring mental alertness and motor coordination, such as driving a car. Indocin (Indomethacin) may also cause headache. Headache which persists despite dosage reduction requires cessation of therapy with Indocin (Indomethacin) .
Indocin (Indomethacin) Precautions
Indocin (Indomethacin) cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids.
The pharmacological activity of Indocin (Indomethacin) in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.
Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including Indocin (Indomethacin) . These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported.
A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with Indocin (Indomethacin) . If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), Indocin (Indomethacin) should be discontinued.
Anemia is sometimes seen in patients receiving NSAIDs, including Indocin (Indomethacin) . This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including Indocin (Indomethacin) , should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia.
NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving Indocin (Indomethacin) who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.
Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.
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 bacterial tests (Ames test and with or without metabolic activation) and a series of tests including the host-mediated assay, sex-linked recessive lethals in , 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.
Safety and effectiveness in pediatric patients 14 years of age and younger has not been established.
Indocin (Indomethacin) 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 (Indomethacin) , 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 (Indomethacin) .
If a decision is made to use indomethacin for pediatric patients two years of age or older, such patients should be monitored closely and periodic assessment of liver function is recommended. There have been cases of hepatotoxicity reported in pediatric patients with juvenile rheumatoid arthritis, including fatalities. If indomethacin treatment is instituted, a suggested starting dose is 1-2 mg/kg/day given in divided doses. Maximum daily dosage should not exceed 3 mg/kg/day or 150‑200 mg/day, whichever is less. Limited data are available to support the use of a maximum daily dosage of 4 mg/kg/day or 150-200 mg/day, whichever is less. As symptoms subside, the total daily dosage should be reduced to the lowest level required to control symptoms, or the drug should be discontinued.
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 and ). 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 ).
Indomethacin may cause confusion or, rarely, psychosis (see ); 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 ).
Indocin (Indomethacin) Adverse Reactions
The adverse reactions for Capsules Indocin (Indomethacin) listed in the following table have been arranged into two groups: (1) incidence greater than 1%; and (2) incidence less than 1%. The incidence for group (1) was obtained from 33 double-blind controlled clinical trials reported in the literature (1,092 patients). The incidence for group (2) was based on reports in clinical trials, in the literature, and on voluntary reports since marketing. The probability of a causal relationship exists between Indocin (Indomethacin) and these adverse reactions, some of which have been reported only rarely.
The adverse reactions reported with Capsules Indocin (Indomethacin) may also occur with use of the suspension.
A rare occurrence of fulminant necrotizing fasciitis, particularly in association with Group Aβ hemolytic streptococcus, has been described in persons treated with non-steroidal anti-inflammatory agents, including indomethacin, sometimes with fatal outcome (see also ).
Indocin (Indomethacin) Overdosage
The following symptoms may be observed following overdosage: nausea, vomiting, intense headache, dizziness, mental confusion, disorientation, or lethargy. There have been reports of paresthesias, numbness, and convulsions.
Treatment is symptomatic and supportive. The stomach should be emptied as quickly as possible if the ingestion is recent. If vomiting has not occurred spontaneously, the patient should be induced to vomit with syrup of ipecac. If the patient is unable to vomit, gastric lavage should be performed. Once the stomach has been emptied, 25 or 50 g of activated charcoal may be given. Depending on the condition of the patient, close medical observation and nursing care may be required. The patient should be followed for several days because gastrointestinal ulceration and hemorrhage have been reported as adverse reactions of indomethacin. Use of antacids may be helpful.
The oral LD of indomethacin in mice and rats (based on 14 day mortality response) was 50 and 12 mg/kg, respectively.
Indocin (Indomethacin) Dosage And Administration
Carefully consider the potential benefits and risks of Indocin (Indomethacin) and other treatment options before deciding to use Indocin (Indomethacin) . Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see ).
After observing the response to initial therapy with Indocin (Indomethacin) , the dose and frequency should be adjusted to suit an individual patient's needs.
Oral Suspension Indocin (Indomethacin) contains 25 mg of indomethacin per 5 mL.
Adverse reactions appear to correlate with the size of the dose of Indocin (Indomethacin) in most patients but not all. Therefore, every effort should be made to determine the smallest effective dosage for the individual patient.
Indocin (Indomethacin) How Supplied
Oral Suspension Indocin (Indomethacin) , 25 mg per 5 mL, is an off-white suspension with a pineapple coconut mint flavor. It is supplied as follows:
Indocin (Indomethacin)
Indocin (Indomethacin)
