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Indomethacin (KVK-Tech, Inc.)

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CAPSULE, EXTENDED RELEASE 500 CAPSULE, EXTENDED RELEASE in 1 BOTTLE (10702-016-50) Label Information
CAPSULE, EXTENDED RELEASE 30 CAPSULE, EXTENDED RELEASE in 1 BOTTLE (10702-016-03) Label Information
CAPSULE, EXTENDED RELEASE 60 CAPSULE, EXTENDED RELEASE in 1 BOTTLE (10702-016-06) Label Information
CAPSULE, EXTENDED RELEASE 90 CAPSULE, EXTENDED RELEASE in 1 BOTTLE (10702-016-09) Label Information
CAPSULE, EXTENDED RELEASE 100 CAPSULE, EXTENDED RELEASE in 1 BOTTLE (10702-016-01) Label Information
CAPSULE, EXTENDED RELEASE 1000 CAPSULE, EXTENDED RELEASE in 1 BOTTLE (10702-016-10) Label Information

Complete Indomethacin Information

  • BOXED WARNING(What is this?)

    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 Extended-release capsules USP 75 cannot be considered a simple analgesic and should not be used in conditions other than those recommended under INDICATIONS AND USAGE.

    Indomethacin is a nonsteroidal, 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:

    Chemical Structure

    Each extended-release capsule, for oral administration contains 75 mg of indomethacin. In addition, each capsule contains the following inactive ingredients: corn starch, D&C Yellow# 10, gelatin, mannitol, povidone, sucrose, talc, and titanium dioxide.

    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 USP 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 USP 75 mg 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 USP 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 Capsules USP 75 mg 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 Capsules USP 75 mg 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 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 75 mg and other treatment options before deciding to use Indomethacin Extended-release Capsules USP 75 mg. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (See WARNINGS).

    Indomethacin Extended-release Capsules USP 75 mg has 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 75 mg 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 , and PRECAUTIONS - Preexisting Asthma ).

    In the setting of coronary artery bypass graft (CABG) surgery (See WARNINGS).


  • WARNINGS:

    CARDIOVASCULAR EFFECTS

    Cardiovascular Thrombotic Events

    Clinical trials 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, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses.

    To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the 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 an NSAID, such as indomethacin, increases the risk of serious gastrointestinal (GI) events (See WARNINGS ).

    Status Post Coronary Artery Bypass Graft (CABG) Surgery

    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. NSAIDs are contraindicated in the setting of CABG (See CONTRAINDICATIONS).

    Post-MI Patients

    Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up.

    Avoid the use of Indomethacin Extended-release Capsules in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If Indomethacin Extended-release Capsules are used in patients with a recent MI, monitor patients for signs of cardiac ischemia.

    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.

    Heart Failure and Edema

    The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death.

    Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of indomethacin may blunt the CV effects of several therapeutic agents used to treat these medical conditions [e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers (ARBs)] (See Drug Interactions ).

    Avoid the use of Indomethacin Extended-release Capsules in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If Indomethacin Extended-release Capsules are used in patients with severe heart failure, monitor patients for signs of worsening 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 intestine, 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 develop 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 for 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 for 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 other 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.

    Hepatic Effects

    Borderline elevations of one or 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 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 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 a 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. Cardiovascular Thrombotic Events

    Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately (See WARNINGS).

    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 hospitalization 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. Heart Failure And Edema

    Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur (See WARNINGS ).

    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 reaction (e.g., difficulty breathing, swelling of the face or 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.

    Drug Interactions

    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 free 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 WARNINGS, Renal Effects ), 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))

    Carcinogensis, Mutagenesis, Impairment of Fertility

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

    Prenancy

    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 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 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.

    In controlled clinical trials, the incidence of adverse reactions to Indomethacin Extended-release Capsules USP 75 mg and equal 24-hour doses of indomethacin capsules were similar.

    Incidence great than 1% Incidence less than 1%

    GASTROINTESTINAL

    nausea* with or without vomiting

    dyspepsia* (including indigestion, heartburn and epigastric pain)

    diarrhea

    abdominal distress or pain constipation                      

    anorexia

    bloating (includes distention)

    flatulence

    peptic ulcer

    gastroenteritis

    rectal bleeding

    proctitis

    single or multiple ulcerations, including  perforation and hemorrhage of the esophagus, stomach,duodenum or small and  large intestines

    Intestinal ulceration associated with stenosis and obstruction

    gastrointestinal bleeding without obvious ulcer  formation and perforation of pre-existing sigmoid lesions (diverticulum, carcinoma, etc.) development of  ulcerative colitis and regional ileitisulcerative stomatitis

    toxic hepatitis and jaundice (some fatal  cases have been   reported)

    CENTRAL NERVOUS SYSTEM

    headache (11.7%)

    dizziness* 

    vertigo

    somnolence 

    depression and fatigue

    including malaise and listlessness)                                                      

    anxiety (includes nervousness)

    muscle weakness

    involuntary muscle movemets insomnia

    muzziness

    psychic disturbances including psychotic episodes

    mental confussion                  

    drowsiness                               

    light-headedness

    syncope

    paresthesia

    aggravation of epilepsy and parkinsonism

    depersonalization

    coma

    peripheral neuropathy convulsions dysarthria                                        

    SPECIAL SENSES

    tinnitus                                   ocular-corneal deposits and retinal disturbances, including those of macula, have been reported in some  patients on prolonged therapy with indomethacin                           

    blurred vision

    diplopia

    hearing disturbances, deafness                                          

    CARDIOVASCULAR

    none                                     

    hypertension

    hypotension

    tachycardia

    chest pain                                        

    congestive heart failure

    arrhythmia; palpitations                                       

    METABOLIC

    none                                     

    edema

    weight gain

    fluid retention

    flushing or sweating                                      

    hyperglycemia

    glycosuria hyperkalemia                                    

    INTEGUMENTARY

    none                                     

    pruritus

    rash; urticaria

    petechiae or ecchymosis                                 

    exfoliative dermatitis

    erythema nodosum

    loss of hair

    Stevens-Johnson syndrome

    erythema multiforme

    toxic epidermal necrolysis                                          

    HEMATOLOGIC

    none                                    

    leukopenia

    bone marrow depression

    anemia secondary to  obvious or occult gastrointestinal

    bleeding                                  

    aplastic anemia

    hemolytic anemia

    agranulocytosis

    thrombocytopenic

    purpura

    disseminated

    intravascular 

    coagulation                                        

    HYPERSENSITIVITY

    none                                            

    acute anaphylaxis

    acute respiratory

    distress

    rapid fall in blood

    pressure resembling a shock

    -like state angioedema                             

    dyspnea

    asthma

    purpura

    angiitis

    pulmonary edema

    fever                                                  

    GENITOURINARY

    none                                   

    hematuria

    vaginal bleeding

    proteinuria

    nephrotic syndrome

    interstitial nephritis                                  

    BUN elevation

    renal insufficiency 

    including renal failure                                                

    MISCELLANEOUS

    none                                       

    epistaxis

    breast changes,

    including enlargement and  

    tenderness,  or gynecomastia                                                                                    

    *  Reactions occurring in 3% to 9% of patients treated with indomethacin. (Those reactions occurring in less than 3% of the patients are unmarked.)

    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 fasciitis, 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 USP 75 mg are available for oral use. Indomethacin Extended-release Capsules USP 75 mg 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 USP 75 mg b.i.d. can be substituted for indomethacin 50 mg capsules t.i.d. Indomethacin Extended-release Capsules USP 75 mg 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 USP 75 mg with food, immediately after meals, or with antacids to reduce gastric irritation.


    Pediatric Use: Indomethacin Extended-release Capsules USP 75 mg 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 disesase; moderate to severe ankylosing spondylitis; and moderate to severe osteoarthritis.


    The following information is provided as background only and refers to immediate-release 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 Indomethacin Extended-release Capsules USP 75 mg.


    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 INCREASE 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 Indomethacin Extended-release Capsules USP 75 mg:

    If Indomethacin Extended-release Capsules USP 75 mg 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 USP 75 mg 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 USP 75 mg may be prescribed as one capsule twice daily.

    If minor adverse effects develop 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 phase 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 tendinitis): Initial Dose: 75 mg to 150mg 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 supplied as yellow opaque cap, natural body with black imprint “K 16” on both cap and body, filled with white pellets.


    Bottles of 30 capsules, NDC 10702-016-03
    Bottles of 60 capsules, NDC 10702-016-06
    Bottles of 90 capsules, NDC 10702-016-09
    Bottles of 100 capsules, NDC 10702-016-01
    Bottles of 500 capsules, NDC 10702-016-50
    Bottles of 1000 capsules, NDC 10702-016-10


    Rx only

    Store at 20° to 25°C (68° to 77°F) with excursions permitted between 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Protect from moisture.


  • Medication Guide for Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

    What is the most important information I should know about medicines called Non-steroidal Anti-inflammatory Drugs (NSAIDs)?

    NSAIDs can cause serious side effects, including:

    Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and may increase:

    ° with increasing doses of NSAIDs

    ° with longer use of NSAIDs

    Do not take NSAIDs right before or after a heart surgery called a "coronary artery bypass graft (CABG)’’.

    Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack.

    Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines:

    ° anytime during use

    ° without warning symptoms

    ° that may cause death

    The risk of getting an ulcer or bleeding increases with:

    ° past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs

    ° taking medicines called "corticosteroids", "anticoagulants", "SSRIs", or "SNRIs"

    ° increasing doses of NSAIDs

    ° longer use of NSAIDs

    ° smoking

    ° drinking alcohol

    ° older age

    ° poor health

    ° advanced liver disease

    ° bleeding problems

    NSAIDs should only be used:

    ° exactly as prescribed

    ° at the lowest dose possible for your treatment

    ° for the shortest time needed

    What are NSAIDs?

    NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps, and other types of short-term pain.

    Who should not take NSAIDs?

    Do not take NSAIDs:

    if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs.

    right before or after heart bypass surgery.

    Before taking NSAIDS, tell your healthcare provider about all of your medical conditions, including if you:

    have liver or kidney problems

    have high blood pressure

    have asthma

    are pregnant or plan to become pregnant. Talk to your healthcare provider if you are considering taking NSAIDs during pregnancy. You should not take NSAIDs after 29 weeks of pregnancy.

    are breastfeeding or plan to breast feed.

    Tell your healthcare provider about all of the medicines you take, including prescription or over-the-counter medicines, vitamins or herbal supplements. NSAIDs and some other medicines can interact with each other and cause serious side effects. Do not start taking any new medicine without talking to your healthcare provider first.

    What are the possible side effects of NSAIDs?

    NSAIDs can cause serious side effects, including:

    See "What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)"?

    new or worse high blood pressure

    heart failure

    liver problems including liver failure

    kidney problems including kidney failure

    low red blood cells (anemia)

    life-threatening skin reactions

    life threatening allergic reactions

    Other side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness.

    Get emergency help right away if you get any of the following symptoms:

    shortness of breath or trouble breathing

    slurred speech

    chest pain

    swelling of the face or throat

    weakness in one part or side of your body

    Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms:

    nausea

    vomit blood

    more tired or weaker than usual

    there is blood in your bowel movement or it is black and sticky like tar

    itching

    diarrhea

    unusual weight gain

    your skin or eyes look yellow

    skin rash or blisters with fever

    indigestion or stomach pain

    swelling of the arms and legs, hands and feet

    flu-like symptoms

    If you take too much of your NSAID, call your healthcare provider or get medical help right away.

    These are not all the possible side effects with NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs.

    Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

    Other information about NSAIDs

    Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines.

    Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days.

    General information about the safe and effective use of NSAIDs

    Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them.

    If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals.

    Manufactured by:

    KVK-TECH INC.

    110 Terry Drive

    Newtown, PA 18940

    KvK logo

    Item ID # 006030/06

    Manufacturer’s Code: 10702        07/15

    For more information, go to www.kvktech.com or call our customer service at 215-579-1842.

    This Medication Guide has been approved by the U.S. Food and Drug Administration.


  • PACKAGE LABEL.PRINCIPAL DISPLAY PANEL – 75 mg Bottle Labels

    Pack Size: 30s

    NDC 10702-016-03

    INDOMETHACIN EXTENDED-RELEASE CAPSULES USP

    75 mg

    PHARMACIST: Please dispense with Medication Guide.

    Rx Only        30 CAPSULES

    KVK-TECH, INC.

    30s

    Pack Size: 60s

    NDC 10702-016-06

    INDOMETHACIN EXTENDED-RELEASE CAPSULES USP

    75 mg

    PHARMACIST: Please dispense with Medication Guide.

    Rx Only    60 CAPSULES

    KVK-TECH, INC.

    60s

    Pack Size: 90s

    NDC 10702-016-09

    INDOMETHACIN EXTENDED-RELEASE CAPSULES USP

    75 mg

    PHARMACIST: Please dispense with Medication Guide.

    Rx Only       90 CAPSULES

    KVK-TECH, INC.

    90s

    Pack Size: 100s

    NDC 10702-016-01

    INDOMETHACIN EXTENDED-RELEASE CAPSULES USP

    75 mg

    PHARMACIST: Please dispense with Medication Guide.

    Rx Only     100 CAPSULES

    KVK-TECH, INC.

    100s

    Pack Size: 500s

    NDC 10702-016-50

    INDOMETHACIN EXTENDED-RELEASE CAPSULES USP

    75 mg

    PHARMACIST: Please dispense with Medication Guide.

    Rx Only      500 CAPSULES

    KVK-TECH, INC.

    500s

    Pack Size: 1000s

    NDC 10702-016-10

    INDOMETHACIN EXTENDED-RELEASE CAPSULES USP

    75 mg

    PHARMACIST: Please dispense with Medication Guide.

    Rx Only      1000 CAPSULES

    KVK-TECH, INC.

    1000s


  • INGREDIENTS AND APPEARANCE
    INDOMETHACIN 
    indomethacin capsule, extended release
    Product Information
    Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:10702-016
    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
    STARCH, CORN (UNII: O8232NY3SJ)  
    D&C YELLOW NO. 10 (UNII: 35SW5USQ3G)  
    GELATIN (UNII: 2G86QN327L)  
    MANNITOL (UNII: 3OWL53L36A)  
    POVIDONE (UNII: FZ989GH94E)  
    SUCROSE (UNII: C151H8M554)  
    TALC (UNII: 7SEV7J4R1U)  
    TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
    Product Characteristics
    Color YELLOW, BLACK Score no score
    Shape CAPSULE Size 22mm
    Flavor Imprint Code K;16
    Contains     
    Packaging
    # Item Code Package Description Marketing Start Date Marketing End Date
    1 NDC:10702-016-03 30 in 1 BOTTLE; Type 0: Not a Combination Product 02/02/2011
    2 NDC:10702-016-06 60 in 1 BOTTLE; Type 0: Not a Combination Product 03/06/2009
    3 NDC:10702-016-09 90 in 1 BOTTLE; Type 0: Not a Combination Product 02/02/2011
    4 NDC:10702-016-01 100 in 1 BOTTLE; Type 0: Not a Combination Product 03/06/2009
    5 NDC:10702-016-50 500 in 1 BOTTLE; Type 0: Not a Combination Product 03/06/2009
    6 NDC:10702-016-10 1000 in 1 BOTTLE; Type 0: Not a Combination Product 03/06/2009
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    ANDA ANDA079175 03/06/2009
    Labeler - KVK-Tech, Inc. (173360061)
    Registrant - Avanthi, Inc. (173360061)
    Establishment
    Name Address ID/FEI Business Operations
    Avanthi, Inc. 173360061 MANUFACTURE(10702-016)