Indomethacin

INDOMETHACIN — indomethacin capsule, extended release
Camber Pharmaceuticals, Inc.

BOXED WARNING

Cardiovascular Thrombotic Events
• Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use [see Warnings and Precautions].
• Indomethacin extended-release capsules are contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications and Warnings].
Gastrointestinal Risk
• NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events (see WARNINGS).

DESCRIPTION

Indomethacin cannot be considered a simple analgesic and should not be used in conditions other than those recommended under INDICATIONS AND USAGE.
Indomethacin is a non-steroidal anti-inflammatory indole derivative designated chemically as 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid. 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. The structural formula is:

IndomethacinERstructure
(click image for full-size original)

C19 H16 ClNO4 M.W. 357.80
Each extended-release capsule, for oral administration contains 75 mg of indomethacin and the following inactive ingredients: sugar spheres, povidone, mannitol, isopropyl alcohol, talc. The hard gelatin shell consists of gelatin, iron oxide yellow, titanium dioxide, sodium lauryl sulfate.
The imprinting ink contains the following: shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia solution, black iron oxide E172 dye and potassium hydroxide.
This product meets USP Drug Release Test 2 Specifications.

CLINICAL PHARMACOLOGY

Indomethacin is a nonsteroidal drug with anti-inflammatory, 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 in vitro. Concentrations are reached during therapy which have been demonstrated to have an effect in vivo 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 has been reported to diminish basal and CO2 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 extended-release capsules (75 mg) are designed to release 25 mg of drug initially and the remaining 50 mg over approximately 12 hours (90% of dose absorbed by 12 hours). Plasma concentrations of indomethacin fluctuate less and are more sustained following administration of indomethacin extended-release capsules than following administration of 25 mg indomethacin capsules given at 4 to 6 hour intervals. In multiple-dose comparisons, the mean daily steady state plasma level of indomethacin attained with daily administration of indomethacin extended-release capsules 75 mg was indistinguishable from that following indomethacin 25 mg capsules given at 0, 6 and 12 hours daily. However, there was a significant difference in indomethacin plasma levels between the two dosage regimens especially after 12 hours.
Controlled clinical studies of safety and efficacy in patients with osteoarthritis have shown that one capsule of indomethacin extended-release was clinically comparable to one 25 mg indomethacin capsule t.i.d.; and in controlled clinical studies in patients with rheumatoid arthritis, one capsule of indomethacin extended-release taken in the morning and one in the evening were clinically indistinguishable from one 50 mg capsule of indomethacin t.i.d.
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.

INDICATIONS & USAGE

Carefully consider the potential benefits and risks of indomethacin extended-release capsules and other treatment options before deciding to use indomethacin extended-release capsules. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS).

Indomethacin extended-release capsules have been found effective in active stages of the following:

1. Moderate to severe rheumatoid arthritis including acute flares of chronic disease.
2. Moderate to severe ankylosing spondylitis.
3. Moderate to severe osteoarthritis.
4. Acute painful shoulder (bursitis and/or tendinitis).
Indomethacin extended-release capsules, USP are not recommended for the treatment of acute gouty arthritis.
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.The use of indomethacin in conjunction with aspirin or other salicylates is not recommended. Controlled clinical studies have shown that the combined use of indomethacin and aspirin 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. (See PRECAUTIONS,Drug Interactions).

CONTRAINDICATIONS

Indomethacin extended-release capsules are contraindicated in patients with known hypersensitivity to indomethacin.
Indomethacin extended-release capsules 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-like reactions to NSAIDs have been reported in such patients (see WARNINGS: Anaphylactoid Reactions, and Precautions: Preexisting Asthma).Indomethacin extended-release capsules is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).

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