Indomethacin Information
Indomethacin () Description
Indomethacin () capsules, USP for oral administration are provided in two dosage strengths which contain either 25 mg or 50 mg of Indomethacin () . Indomethacin () is a non-steroidal anti-inflammatory indole derivative designated chemically as 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1 -indole-3-acetic acid.
The structural formula is:
CHClNO M.W. 357.79
Indomethacin () , USP 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.
Each capsule for oral administration contains 25 mg or 50 mg of Indomethacin () and the following inactive ingredients: colloidal silicon dioxide, FD&C Blue No. 1, D&C Yellow No. 10, gelatin, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate, sodium starch glycolate and titanium dioxide.
The imprinting ink contains the following: black iron oxide, butyl alcohol, dehydrated alcohol, isopropyl alcohol, potassium hydroxide, propylene glycol, shellac, strong ammonia solution and purified water.
Indomethacin () Clinical Pharmacology
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.
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.
Indomethacin () has been shown to be an effective anti-inflammatory agent, appropriate for long-term use in rheumatoid arthritis, ankylosing spondylitis, and osteoarthritis.
Indomethacin () affords relief of symptoms; it does not alter the progressive course of the underlying disease.
Indomethacin () suppresses inflammation in rheumatoid arthritis as demonstrated by relief of pain, and reduction of fever, swelling and tenderness. Improvement in patients treated with 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. 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.
Indomethacin () capsules 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 Indomethacin () capsules 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 Indomethacin () capsules are virtually 100% bioavailable, with 90% of the dose absorbed within 4 hours. A single 50 mg dose of Indomethacin () oral suspension was found to be bioequivalent to a 50 mg 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 mg 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 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 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.
Indomethacin () Indications And Usage
Carefully consider the potential benefits and risks of Indomethacin () capsules and other treatment options before deciding to use Indomethacin () . Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see ).
Indomethacin () capsules have been found effective in active stages of the following:
Indomethacin () Contraindications
Indomethacin () is contraindicated in patients with known hypersensitivity to Indomethacin () or the excipients (see ).
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 ).
Indomethacin () is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery (see ).
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 non-steroidal 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 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 ).
Indomethacin () may aggravate depression or other psychiatric disturbances, epilepsy, and parkinsonism, and should be used with considerable caution in patients with these conditions. If severe CNS adverse reactions develop, Indomethacin () should be discontinued.
Indomethacin () may cause drowsiness; therefore, patients should be cautioned about engaging in activities requiring mental alertness and motor coordination, such as driving a car. Indomethacin () may also cause headache. Headache which persists despite dosage reduction requires cessation of therapy with Indomethacin () .
Indomethacin () Precautions
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 Indomethacin () in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.
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 to 110 weeks) and the mouse (dosing period 62 to 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 have not been established.
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 Indomethacin () capsules, side effects in pediatric patients were comparable to those reported in adults. Experience in pediatric patients has been confined to the use of Indomethacin () capsules.
If a decision is made to use Indomethacin () for pediatric patients 2 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 to 2 mg/kg/day given in divided doses. Maximum daily dosage should not exceed 3 mg/kg/day or 150 to 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 to 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 ).
Indomethacin () Adverse Reactions
The adverse reactions for Indomethacin () capsules listed in the following table have been arranged into two groups: (1) incidence greater than 1%; and (2) incidence less than 1%. The incidence for group (1) was obtained from 33 double-blind controlled clinical trials reported in the literature (1,092 patients). The incidence for group (2) was based on reports in clinical trials, in the literature, and on voluntary reports since marketing. The probability of a causal relationship exists between Indomethacin () and these adverse reactions, some of which have been reported only rarely.
GASTROINTESTINAL
CENTRAL NERVOUS SYSTEM
1
SPECIAL SENSES
CARDIOVASCULAR
METABOLIC
INTEGUMENTARY
HEMATOLOGIC
HYPERSENSITIVITY
GENITOURINARY
MISCELLANEOUS
1
GASTROINTESTINAL
CENTRAL NERVOUS SYSTEM
SPECIAL SENSES
CARDIOVASCULAR
METABOLIC
INTEGUMENTARY
HEMATOLOGIC
HYPERSENSITIVITY
GENITOURINARY
MISCELLANEOUS
Other reactions have been reported but occurred under circumstances where a causal relationship could not be established. However, in these rarely reported events, the possibility cannot be excluded. Therefore, these observations are being listed to serve as alerting information to physicians:
A rare occurrence of fulminant necrotizing fasciitis, particularly in association with Group A β-hemolytic streptococcus, has been described in persons treated with non-steroidal anti-inflammatory agents, including Indomethacin () , sometimes with fatal outcome (see also ).
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 g 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.
Indomethacin () Dosage And Administration
Carefully consider the potential benefits and risks of Indomethacin () and other treatment options before deciding to use Indomethacin () . Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see ).
After observing the response to initial therapy with Indomethacin () , the dose and frequency should be adjusted to suit an individual patient's needs.
Indomethacin () is available as 25 mg and 50 mg capsules.
Adverse reactions appear to correlate with the size of the dose of Indomethacin () in most patients but not all. Therefore, every effort should be made to determine the smallest effective dosage for the individual patient.
Indomethacin () How Supplied
Indomethacin () capsules USP are available containing either 25 mg or 50 mg of Indomethacin () , USP.
The 25 mg capsule is a size ‘3’ two piece opaque green hard gelatin capsule imprinted with ‘G406’ on body and ‘G’ on cap, filled with white-to off-white granular powder. They are available as follows:
Bottles of 100 capsules NDC 68462-406-01Bottles of 1000 capsules NDC 68462-406-10
The 50 mg capsule is a size ‘1’ two piece opaque green hard gelatin capsules imprinted with ‘G302’ on body and ‘G’ on cap filled with white to off-white granular powder. They are available as follows:
Bottles of 100 capsules NDC 68462-302-01Bottles of 500 capsules NDC 68462-302-05
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