INDOMETHACIN capsule, extended release

Indomethacin by

Drug Labeling and Warnings

Indomethacin by is a Prescription medication manufactured, distributed, or labeled by Lake Erie Medical & Surgical Supply DBA Quality Care Products LLC, Amneal Pharmaceuticals. Drug facts, warnings, and ingredients follow.

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BOXED WARNING

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Cardiovascular Risk NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at a greater risk. (See WARNINGS.) Indomethacin is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see 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 INDICATION 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 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:

M.W. 357.80                                                                                                            C19H16ClNO4

Each extended-release capsule, for oral administration contains 75 mg of indomethacin. In addition, each capsule contains the following inactive ingredients: ammonia, black iron oxide, butyl alcohol, corn starch, dehydrated alcohol, FD&C Blue No. 1, FD&C Green No. 3, FD&C Yellow No. 5, FD&C Red No. 40, gelatin, isopropyl alcohol, lactose monohydrate, potassium hydroxide, povidone, propylene glycol, shellac, sucrose and talc.

This Product meets the USP Drug Release Test 2 Specifications.

CLINICAL PHARMACOLOGY

Indomethacin is a non-steroidal 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 fluctuates 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 hours Intervals. In multiple dose comparisons, the mean daily steady plasma levels 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. Indomethacn 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 desmethyl-desbenzoyl 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 AND USAGE

Carefully consider the potential benefits and risks of Indomethacin Extended-Release Capsules, USP and other treatment options before deciding to use Indomethacin Extended-Release Capsules, USP. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS).

Indomethacin Extended-Release Capsules, USP 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 sever osteoarthritis.

4. Acute painful shoulder (bursitis and/or tendonitis).

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 sever 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 product 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 are contraindicated for the treatment of peri-operative pain in the setting of coronary artier bypass graft (CABG) surgery (see WARNINGS).

WARNINGS

CARDIOVASCULAR EFFECTS

Cardiovascular Thrombotic Events

Clinical trails of several COX-2 selective and nonselective NSAIDS of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with a NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur.

There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and a NSAID does increase the risk of serious GI events (see GI WARNINGS).

Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see CONTRAINDICATIONS).

Hypertension

NSAIDs, including Indomethacin Extended Release Capsules, can lead to onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including Indomethacin Extended-Release Capsules, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy.

Congestive Heart Failure and Edema

Fluid retention edema have been observed in some patients taking NSAIDs. Indomethacin Extended-Release Capsules should be used with caution in patients with fluid retention or heart failure.

Gastrointestinal Effects – Risk of Ulceration, Bleeding, and Perforation

NSAIDs, including Indomethacin Extended-Release Capsules, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestines, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients, who development a serious upper GI adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk.

NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDS include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population.

To minimize the potential risk of an adverse GI event in patients treated with a NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered.

Renal Effects

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 overt 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, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.

Advanced Renal Disease

No information is available from controlled clinical studies regarding the use of Indomethacin Extended-Release Capsules in patients with advanced renal disease. Therefore, treatment with Indomethacin Extended-release Capsules is not recommended in these patients with advanced renal disease. If Indomethacin Extended-Release Capsules therapy must be initiated, close monitoring of the patient’s renal function is advisable.

Anaphylactoid Reactions

As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to Indomethacin Extended-Release Capsules. Indomethacin Extended-Release Capsules should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see CONTRAINDICATIONS and PRECAUTIONS – Preexisting Asthma). Emergency help should be sought in cases where an anaphylactoid reaction occurs.

Skin Reactions

NSAIDs, including Indomethacin Extended-Release Capsules, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any sign of hypersensitivity.

Pregnancy

In late pregnancy, as with other NSAIDs, Indomethacin Extended-Release Capsules should be avoided because it may cause premature closure of the ductus arteriosus.

PRECAUTIONS

General

Indomethacin Extended-Release Capsules 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 Extended-Release Capsules in reducing (fever and) inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.

This product contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin sensitivity.

Hepatic Effects

Borderline elevations of one of more liver tests may occur in up to 15% of patients taking NSAIDs including Indomethacin Extended-Release Capsules. 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 sever hepatic reaction while on therapy with Indomethacin Extended-Release Capsules. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), Indomethacin Extended-Release Capsules should be discontinued.

Hematological Effects

Anemia is sometimes seen in patients receiving NSAIDs, including Indomethacin Extended-Release Capsules. 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 Indomethacin Extended-Release Capsules, 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 Indomethacin Extended-Release Capsules who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.

Preexisting Asthma

Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross-reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients. Indomethacin Extended-Release Capsules should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.

INFORMATION FOR PATIENTS

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.

1.  Indomethacin Extended-Release Capsules, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS, Cardiovascular Effects).

2.  Indomethacin Extended-Release Capsules, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS, Gastrointestinal Effects: Risk of Ulceration, Bleeding and Perforation).

3.  Indomethacin Extended-Release Capsules, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible.

4.  Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians.

5. Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy.

6.  Patients should be informed of the signs of an anaphylactoid (e.g., difficulty breathing, swelling of the face of throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS).

7.  In late pregnancy, as with other NSAIDs, Indomethacin Extended-Release Capsules should be avoided because it will cause premature closure of the ductus arteriosus.

Laboratory Tests

Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs, should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, Indomethacin Extended-release Capsules should be discontinued.

                        

Ace-inhibitors

Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors.

Aspirin

[When Indomethacin Extended-Release Capsules are administered with aspirin, its protein binding is reduced, although the clearance of fee Indomethacin Extended-Release Capsules is not altered. The clinical significance of this interaction is not known; however,] as with other NSAIDs, concomitant administration of Indomethacin and aspirin is not generally recommended because of the potential of increased adverse effects.

Furosemide

Clinical studies, as well as post marketing observations, have shown that Indomethacin Extended-Release Capsules can reduce the natriuretic effect-of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see PRECAUTIONS, Renal Effect), as well as to assure diuretic efficacy.

Lithium

NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%.

These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity.

Methotrexate

NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate.

Warfarin

The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone.

Drug/Laboratory Test Interactions

Only if positive interactions have been observed. (see 201.57 (f)(4)(N))

Carcinogenesis, Mutagenesis, Impairment of Fertility

Usually only if significant findings have been observed. (see 201.57 (f)(5))

Pregnancy

Teratogenic Effects. Pregnancy Category C.

Reproductive studies conducted in rats and rabbits have not demonstrated evidence of developmental abnormalities. However, animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies in pregnant women.

Nonteratogenic Effects

Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of the ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided.

Labor and Delivery

In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of Indomethacin Extended-Release Capsules on labor and delivery in pregnant women are unknown.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Indomethacin Extended-Release Capsules, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 14 years old, have not been established.

Geriatric Use

As with any NSAIDs, caution should be exercised in treating the elderly (65 years and older).

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 doubleblind controlled clinical trails 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.

In controlled clinical trials, the incidence of adverse reactions to Indomethacin Extended-Release Capsules and equal 24-hour doses of indomethacin capsules were similar.

Incidence greater than 1%	Incident less than 1%
*Reactions occurring in 3% to 9% of patients treated with Indomethacin. (Those reactions occurring in less than 3% of the patients are unmarked.)
GASTROINTESTINAL
nausea* with or without	anorexia	Gastrointestinal bleeding without
vomiting	bloating (including distention)	obvious ulcer formation and
Dyspepsia * (including	flatulence	Perforation of preexisting sigmoid
indigestion, heartburn and	peptic ulcer	lesions (diverticulum, carcinoma,
epigastric pain)	gastroenteritis	etc.) development of ulcerative
diarrhea	rectal bleeding	and regional ileitis
abdominal distress or pain	procitis	ulcerative stomatitis
Colitis constipation	single or multiple ulcerations.	toxic hepatitis and jaundice (some
	including perforation and	fatal cases have been reported)
	hemorrhage of the esophagus,
	stomach, duodenum or small
	and large intestines
CENTRAL NERVOUS SYSTEM
headache (11.7%)	anxiety (includes nervousness)	light-headedness
dizziness	muscle weakness	syncope
vertigo	involuntary muscle movements	parathesia
somnolence	insomnia	aggravation of epilepsy and
depression and fatigue	muzziness	parkinsonism
(including malaise and	psychic disturbances including	depersonalization
listlessness)	psychotic episodes	coma
	mental confusion	peripheral neuropathy
	drowsiness	convulsions
		dysarthria
SPECIAL SENSES
tinnitus	ocular-corneal deposits and	blurred vision
	retinal disturbances, including	diplopia
	those of macula, have been	Hearing disturbances, deafness
	reported in some patients on
	prolonged therapy with
	Indomethacin
CARDIOVASCULAR
none	hypertension	congestive heart failure
	hypotension	arrhythmia; palpitations
	tachycardia
	chest pain
METABOLIC
none	edema	hyperglycemia
	weight gain	glycosuria
	fluid retention	hyperkalemia
	flushing or sweating
INTEGUMENTARY
none	pruritus	exfoliate dermatitis
	rash; urticaria	erythema nodosum
	petechiae or ecchymosis	loss of hair
		Stevens-Johnson syndrome
		erythema multiforme
		toxic epidermal necrolysis
HEMATOLOGIC
none	leukopemia	aplastic anemia
	bone marrow depression	demolytic anemia
	anemia secondary to obvious or	agranulocytosis
	occult gastrointestinal bleeding	thrombocytopenic purpura
		disseminated intravascular
		coagulation
HYPERSENSITIVITY
none	acute anaphylaxis	dyspnea
	acute respiratory distress	asthma
	rapid fall in blood pressure	purpura
	resembling a shock-like state	angilitis
	angioedema	pulmonary edema
GENITOUINARY
none	hematuria	BUN elevation
	vaginal bleeding	renal insufficiency including
	proteinuria	renal failure
	nephrotic syndrome
	interstitial nephritis
MISCELLANEOUS
none	epistasis
	breast changes, including
	enlargement or tenderness, or
	gynomastia

Causal Relationship Unknown:  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 lasciitis, particularly in association with Group A β-hemolytic streptococcus, has been described in persons treated with nonsteroidal anti-inflammatory agents, including indomethacin, sometimes with fatal outcome (see also PRECAUTIONS, General).

Cardiovascular:  Thrombophlebitis.

Hematologic:  Although there have been several reports of leukemia, the supporting information is weak.

Genitourinary: Urinary frequency.

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 LD50 of indomethacin in mice and rats (based on 14 day mortality response) was 50 and 12 mg/kg, respectively.

DOSAGE AND ADMINISTRATION

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 75 mg are available for oral use. Indomethacin Extended-Release Capsules can be administered once a day and can be substituted for indomethacin 25 mg capsules t.i.d. However, there will be significant difference between the two dosage regimens in indomethacin blood levels, especially after 12 hours (see CLINICAL PHARMACOLOGY). In addition, Indomethacin Extended-Release Capsules 75 mg b.i.d. can be substituted for indomethacin 50 mg capsules t.i.d. Indomethacin Extended-Release Capsules may be substituted for all the indications of indomethacin capsules except acute gouty arthritis.

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.

Always give Indomethacin Extended-Release Capsules 75 mg with food, immediately after meals, or with antacids to reduce gastric irritation.

Pediatric Use:  Indomethacin ordinarily should not be prescribed for children 14 years of age and under (see WARNINGS).

Adult Use:  Dosage Recommendations for Active Stages of the Following:

1.  Moderate to severe rheumatoid arthritis, including acute flares of chronic disease; moderate to sever ankylosing spondylitis; and moderate to sever osteoarthritis.

The following information is provided as background only and refers to immediate-released Indomethacin capsules (25 mg or 50 mg)

• Suggested Dosage:

• The following recommendations on dosing pertain to immediate-release indomethacin capsules USP, and provide important information regarding the dosage and administration of indomethacin. The prescriber should be aware of this information when considering and prescribing extended-release indomethacin.

• Indomethacin capsules 25 mg b.i.d. or t.i.d. If this is well tolerated, increase the daily dosage by 25 or 50 mg, if required by continuing symptoms at weekly intervals until a satisfactory response is obtained or until a total daily dose of 150-200 mg is reached. DOSES ABOVE THIS AMOUNT GENERALLY DO NOT INCREAS THE EFFECTIVENESS OF THE DRUG.

• In patients who have persistent night pain and/or morning stiffness, the giving of a large portion, up to a maximum of 100 mg, of the total daily dose at bedtime, either orally or by rectal suppositories, may be helpful in affording relief. The total daily dose should not exceed 200 mg. In acute flares of chronic rheumatoid arthritis, it may be necessary to increase the dosage by 25 mg or, if required, by 50 mg daily.

The following information refers to Extended-release Indomethacin Capsules (75 mg):

• If Indomethacin Extended-Release Capsules are used for initiating indomethacin treatment, one capsule daily should be the usual starting dose in order to observe patient tolerance since 75 mg per day is the maximum recommended starting dose for indomethacin (see above). If indomethacin Extended-Release Capsules are used to increase the daily dose, patients should be observed for possible signs and symptoms of intolerance since the daily increment will exceed the daily increment recommended for other dosage forms. For patients who require 150 mg of indomethacin per day and have demonstrated acceptable tolerance. Indomethacin Extended-release Capsules 75 mg may be prescribed as one capsule twice daily.

• If minor adverse effects develops as the dosage is increased, reduce the dosage rapidly to a tolerated dose and OBSERVE THE PATIENT CLOSELY.

• If severe adverse reactions occur, STOP THE DRUG. After the acute phrase of the disease is under control, an attempt to reduce the daily dose should be made repeatedly until the patient is receiving the smallest effective dose or the drug is discontinued.

• Careful instructions to, and observations of, the individual patient are essential to the prevention of serious, irreversible, including fatal, adverse reactions.

• As advancing years appear to increase the possibility of adverse reactions, Indomethacin Extended-Release Capsules should be used with greater care in the aged.

• 2.  Acute painful shoulder (bursitis and/or tendonitis). Initial dose:  75 mg to 150 mg daily. When 150 mg is prescribed, give as one capsule twice daily.

• The drug should be discontinued after the signs and symptoms of inflammation have been controlled for several days. The usual course of therapy is 7 to 14 days.

HOW SUPPLIED

Indomethacin Extended-Release Capsules, USP 75 mg are size “2” coni-snap, empty hard gelatin capsules with natural clear body imprinted “506” and blue translucent cap imprinted “AMNEAL” with black ink.

They are available as follows:

Bottles of 30:     NDC: 65162-506-03

Bottles of 60:     NDC: 65162-506-06

Bottles of 90:     NDC: 65162-506-09

Bottles of 100:   NDC: 65162-506-10

Bottles of 500:   NDC: 65162-506-50

Bottles of 1000: NDC: 65162-506-11

Rx only

Storage: Store at 20º to 25ºC (68 º to 77ºF) [See USP Controlled Room Temperature]. Protect from moisture.

PRINCIPAL DISPLAY PANEL

image of label

INGREDIENTS AND APPEARANCE

INDOMETHACIN 
indomethacin capsule, extended release

Product Information
Product Type	HUMAN PRESCRIPTION DRUG	Item Code (Source)	NDC: 49999-371(NDC:65162-506)
Route of Administration	ORAL

Active Ingredient/Active Moiety
Ingredient Name	Basis of Strength	Strength
INDOMETHACIN (UNII: XXE1CET956) (INDOMETHACIN - UNII:XXE1CET956)	INDOMETHACIN	75 mg

Inactive Ingredients
Ingredient Name	Strength
AMMONIA (UNII: 5138Q19F1X)
FERROSOFERRIC OXIDE (UNII: XM0M87F357)
BUTYL ALCOHOL (UNII: 8PJ61P6TS3)
STARCH, CORN (UNII: O8232NY3SJ)
ALCOHOL (UNII: 3K9958V90M)
FD&C BLUE NO. 1 (UNII: H3R47K3TBD)
FD&C GREEN NO. 3 (UNII: 3P3ONR6O1S)
FD&C YELLOW NO. 5 (UNII: I753WB2F1M)
FD&C RED NO. 40 (UNII: WZB9127XOA)
GELATIN (UNII: 2G86QN327L)
ISOPROPYL ALCOHOL (UNII: ND2M416302)
LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)
POTASSIUM HYDROXIDE (UNII: WZH3C48M4T)
POVIDONE (UNII: FZ989GH94E)
PROPYLENE GLYCOL (UNII: 6DC9Q167V3)
SHELLAC (UNII: 46N107B71O)
SUCROSE (UNII: C151H8M554)
TALC (UNII: 7SEV7J4R1U)

Product Characteristics
Color	white (clear)	Score	no score
Shape	CAPSULE	Size	18mm
Flavor		Imprint Code	506;AMNEAL
Contains

Packaging
#	Item Code	Package Description	Marketing Start Date	Marketing End Date
1	NDC: 49999-371-30	30 in 1 BOTTLE

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA091549	11/21/2011

Labeler - Lake Erie Medical & Surgical Supply DBA Quality Care Products LLC (831276758)

Establishment
Name	Address	ID/FEI	Business Operations
Amneal Pharmaceuticals		831227777	ANALYSIS, LABEL, MANUFACTURE, PACK

Establishment
Name	Address	ID/FEI	Business Operations
Lake Erie Medical & Surgical Supply DBA Quality Care Products LLC		831276758	relabel, repack