ADVERSE REACTIONS SECTION.

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 causal relationship exists between indomethacin and these adverse reactions, some of which have been reported only rarely.Incidence greater than 1%GASTROINTESTINALnausea1 with or without vomitingdyspepsia1 (including indigestion, heartburn and epigastric pain)Diarrheaabdominal distress or painconstipationCENTRAL NERVOUS SYSTEM headache (11.7%)dizziness1 vertigosomnolencedepression and fatigue (including malaise and listlessness)SPECIAL SENSES tinnitusCARDIOVASCULAR noneMETABOLICnoneINTEGUMENTARYnoneHEMATOLOGICnoneHYPERSENSITIVITYnoneGENITOURINARYnoneMISCELLANEOUSnone1 Reactions occurring in 3% to 9% of patients treated with indomethacin. (Those reactions occurring in less than 3% of the patients are unmarked.)Incidence less than 1%GASTROINTESTINALanorexiabloating (includes distention)flatulencepeptic ulcergastroenteritisrectal bleedingproctitissingle or multiple ulcerations, including perforation and hemorrhage of the esophagus, stomach, duodenum or small and large intestinesintestinal ulceration associated with stenosis and obstruction gastrointestinal bleeding without obvious ulcer formation and perforation of preexisting sigmoid lesions (diverticulum, carcinoma, etc.) development of ulcerative colitis and regional ileitisulcerative stomatitistoxic hepatitis and jaundice (some fatal cases have been reported)intestinal strictures (diaphragms)CENTRAL NERVOUS SYSTEM anxiety (includes nervousness)muscle weaknessinvoluntary muscle movementsinsomniamuzzinesspsychic disturbances including psychotic episodesmental confusiondrowsinesslight-headednesssyncopeparesthesiaaggravation of epilepsy and parkinsonismdepersonalizationcomaperipheral neuropathyconvulsionsdysarthriaSPECIAL SENSES ocular-corneal deposits and retinal disturbances, including those of the macula, have been reported in some patients on prolonged therapy with indomethacinblurred visiondiplopiahearing disturbances, deafnessCARDIOVASCULAR congestive heart failurehypertensionhypotensiontachycardiachest painarrhythmia; palpitationsMETABOLIC edemaweight gainfluid retentionflushing or sweatinghyperglycemiaglycosuriahyperkalemiaINTEGUMENTARY pruritusrash; urticariapetechiae or ecchymosisexfoliative dermatitiserythema nodosumloss of hairStevens-Johnson Syndromeerythema multiformetoxic epidermal necrolysisHEMATOLOGIC leucopeniabone marrow depressionanemia secondary to obvious or occult gastrointestinal bleedingaplastic anemiahemolytic anemiaagranulocytosisthrombocytopenic purpuradisseminated intravascular coagulationHYPERSENSITIVITY acute anaphylaxisacute respiratory distressrapid fall in blood pressure resembling shock-like stateangioedemadyspneaasthmapurpuraangiitispulmonary edemafeverGENITOURINARY hematuriavaginal bleedingproteinuria, nephrotic syndrome, interstitial nephritisBUN elevationrenal insufficiency, including renal failureMISCELLANEOUS epistaxisbreast changes, including enlargement and tenderness, or gynecomastiaCausal Relationship UnknownOther reactions have been reported but occurred under circumstances where 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:Cardiovascular: thrombophlebitisHematologic: Although there have been several reports of leukemia, the supporting information is weak.Genitourinary: urinary frequencyA rare occurrence of fulminant necrotizing fasciitis, particularly in association with Group -hemolytic streptococcus, has been described in persons treated with non-steroidal anti-inflammatory agents, including indomethacin, sometimes with fatal outcome (see also PRECAUTIONS: General).

BOXED WARNING SECTION.

Cardiovascular RiskNSAIDS 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 greater risk (see WARNINGS).Indomethacin is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).Gastrointestinal RiskNSAIDs 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).. 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 greater risk (see WARNINGS).. Indomethacin is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).. 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).

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. Indomethacin is non-steroidal anti-inflammatory drug (NSAID) that exhibits antipyretic and analgesic properties. Its mode of action, like that of other anti-inflammatory drugs, is not known. However, its therapeutic action is not due to pituitary-adrenal stimulation.Indomethacin is 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 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 reduction in joint swelling, average number of joints involved, and morning stiffness; by increased mobility as demonstrated by decrease in walking time; and by improved functional capability as demonstrated by an increase in grip strength. Indomethacin may enable the reduction of steroid dosage in patients receiving steroids for the more severe forms of rheumatoid arthritis. In such instances the steroid dosage should be reduced slowly and the patients followed very closely for any possible adverse effects.Indomethacin has been reported to diminish basal and 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 capsules have been found effective in relieving the pain, reducing the fever, swelling, redness, and tenderness of acute gouty arthritis (see INDICATIONS AND USAGE).Following single oral doses of indomethacin capsules 25 mg or 50 mg, indomethacin is readily absorbed, attaining peak plasma concentrations of about and mcg/mL, respectively, at about hours. Orally administered indomethacin capsules are virtually 100% bioavailable, with 90% of the dose absorbed within hours. single 50 mg dose of indomethacin oral suspension was found to be bioequivalent to 50 mg indomethacin capsule when each was administered with food.Indomethacin is eliminated via renal excretion, metabolism, and biliary excretion. Indomethacin undergoes appreciable enterohepatic circulation. The mean half-life of indomethacin is estimated to be about 4.5 hours. With typical therapeutic regimen of 25 mg or 50 mg t.i.d., the steady-state plasma concentrations of indomethacin are an average 1.4 times those following the first dose.Indomethacin exists in the plasma as the parent drug and its desmethyl, desbenzoyl, and desmethyl-desbenzoyl metabolites, all in the unconjugated form. About 60 of an oral dosage is recovered in urine as drug and metabolites (26 as indomethacin and its glucuronide), and 33 is recovered in feces (1.5 as indomethacin).About 99% of indomethacin is bound to protein in plasma over the expected range of therapeutic plasma concentrations. Indomethacin has been found to cross the blood-brain barrier and the placenta.

CONTRAINDICATIONS SECTION.

CONTRAINDICATIONS. Indomethacin Capsule, USP is contraindicated in patients with known hypersensitivity to indomethacin or the excipients (see DESCRIPTION).Indomethacin Capsule, USP should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic/anaphylactoid reactions to NSAIDs have been reported in such patients (see WARNINGS: Anaphylactic/Anaphylactoid Reactions, and PRECAUTIONS: General: Preexisting Asthma).Indomethacin Capsule, USP is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).

DESCRIPTION SECTION.

DESCRIPTION. Indomethacin Capsules, USP for oral administration are provided in two dosage strengths which contain either 25 mg or 50 mg of indomethacin. Indomethacin is non-steroidal anti-inflammatory indole derivative designated chemically as 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid.The structural formula is: C19H16ClNO4 M.W. 357.79Indomethacin, USP is practically insoluble in water and sparingly soluble in alcohol. It has pKa of 4.5 and is stable in neutral or slightly acidic media and decomposes in strong alkali.Each capsule for oral administration contains 25 mg or 50 mg of indomethacin and the following inactive ingredients: lactose monohydrate, sodium lauryl sulphate, sodium starch glycolate, colloidal silicon dioxide, magnesium stearate. The hard gelatin shell consists of gelatin, titanium dioxide USP, FD C Blue 1, & Yellow 10. The capsules are printed with black ink containing black iron oxide E172 dye.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. Carefully consider the potential benefits and risks of indomethacin and other treatment options before deciding to use indomethacin. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS).After observing the response to initial therapy with indomethacin, the dose and frequency should be adjusted to suit an individual patients needs.Indomethacin is available as 25 mg and 50 mg capsules.Adverse reactions appear to correlate with the size of the dose of indomethacin in most patients but not all. Therefore, every effort should be made to determine the smallest effective dosage for the individual patient.Pediatric UseIndomethacin ordinarily should not be prescribed for pediatric patients 14 years of age and under (see WARNINGS).Adult UseDosage Recommendations for Active Stages of the Following:Moderate to severe rheumatoid arthritis including acute flares of chronic disease; moderate to severe ankylosing spondylitis; and moderate to severe osteoarthritis.Suggested Dosage: Indomethacin capsules 25 mg b.i.d. or t.i.d. If this is well tolerated, increase the daily dosage by 25 mg or by 50 mg, if required by continuing symptoms, at weekly intervals until satisfactory response is obtained or until total daily dose of 150 mg to 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 large portion, up to maximum of 100 mg, of the total daily dose at bedtime 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. If minor adverse effects develop as the dosage is increased, reduce the dosage rapidly to 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 should be used with greater care in the elderly (see PRECAUTIONS: Geriatric Use). Acute painful shoulder (bursitis and/or tendinitis).Initial Dose: 75 mg to 150 mg daily in or divided doses. The drug should be discontinued after the signs and symptoms of inflammation have been controlled for several days. The usual course of therapy is to 14 daysAcute gouty arthritis.Suggested Dosage: Indomethacin capsules 50 mg t.i.d. until pain is tolerable. The dose should then be rapidly reduced to complete cessation of the drug. Definite relief of pain has been reported within to hours. Tenderness and heat usually subside in 24 to 36 hours, and swelling gradually disappears in to days.. Moderate to severe rheumatoid arthritis including acute flares of chronic disease; moderate to severe ankylosing spondylitis; and moderate to severe osteoarthritis.Suggested Dosage: Indomethacin capsules 25 mg b.i.d. or t.i.d. If this is well tolerated, increase the daily dosage by 25 mg or by 50 mg, if required by continuing symptoms, at weekly intervals until satisfactory response is obtained or until total daily dose of 150 mg to 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 large portion, up to maximum of 100 mg, of the total daily dose at bedtime 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. If minor adverse effects develop as the dosage is increased, reduce the dosage rapidly to 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 should be used with greater care in the elderly (see PRECAUTIONS: Geriatric Use). Acute painful shoulder (bursitis and/or tendinitis).Initial Dose: 75 mg to 150 mg daily in or divided doses. The drug should be discontinued after the signs and symptoms of inflammation have been controlled for several days. The usual course of therapy is to 14 days. Acute gouty arthritis.Suggested Dosage: Indomethacin capsules 50 mg t.i.d. until pain is tolerable. The dose should then be rapidly reduced to complete cessation of the drug. Definite relief of pain has been reported within to hours. Tenderness and heat usually subside in 24 to 36 hours, and swelling gradually disappears in to days.

GENERAL PRECAUTIONS SECTION.

General. Indomethacin cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if decision is made to discontinue corticosteroids.The pharmacological activity of indomethacin in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.Hepatic EffectsBorderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs, including indomethacin. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported.A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test values has occurred, should be evaluated for evidence of the development of more severe hepatic reaction while on therapy with indomethacin. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), indomethacin should be discontinued.Hematological EffectsAnemia is sometimes seen in patients receiving NSAIDs, including indomethacin. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including indomethacin, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia.NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving indomethacin who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.. 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 non-steroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, indomethacin should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.

HOW SUPPLIED SECTION.

HOW SUPPLIED. Product: 50090-0051NDC: 50090-0051-0 20 CAPSULE in BOTTLE.

INDICATIONS & USAGE SECTION.

INDICATIONS AND USAGE. Carefully consider the potential benefits and risks of indomethacin capsules and other treatment options before deciding to use indomethacin. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS).Indomethacin Capsule, USP has been found effective in active stages of the following:Moderate to severe rheumatoid arthritis including acute flares of chronic disease.Moderate to severe ankylosing spondylitis.Moderate to severe osteoarthritis.Acute painful shoulder (bursitis and/or tendinitis).Acute gouty arthritis.. Moderate to severe rheumatoid arthritis including acute flares of chronic disease.. Moderate to severe ankylosing spondylitis.. Moderate to severe osteoarthritis.. Acute painful shoulder (bursitis and/or tendinitis).. Acute gouty arthritis.

OVERDOSAGE SECTION.

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 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.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

Indomethacin. 8c496175-figure-01. Label Image.

PRECAUTIONS SECTION.

PRECAUTIONS. General. Indomethacin cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if decision is made to discontinue corticosteroids.The pharmacological activity of indomethacin in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.Hepatic EffectsBorderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs, including indomethacin. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported.A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test values has occurred, should be evaluated for evidence of the development of more severe hepatic reaction while on therapy with indomethacin. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), indomethacin should be discontinued.Hematological EffectsAnemia is sometimes seen in patients receiving NSAIDs, including indomethacin. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including indomethacin, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia.NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving indomethacin who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.. 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 non-steroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, indomethacin 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.Indomethacin, 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).Indomethacin, 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 signs 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).Indomethacin, 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.Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians.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.Patients should be informed of the signs of an anaphylactic/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).In late pregnancy, as with other NSAIDs, indomethacin should be avoided because it may cause premature closure of the ductus arteriosus.. Indomethacin, 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).. Indomethacin, 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 signs 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).. Indomethacin, 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.. Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians.. 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.. Patients should be informed of the signs of an anaphylactic/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).. In late pregnancy, as with other NSAIDs, indomethacin should be avoided because it may 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 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 should be discontinued.. Drug Interactions. ACE Inhibitors and Angiotensin II AntagonistsReports suggest that NSAIDs may diminish the antihypertensive effect of ACE inhibitors and angiotensin II antagonists. Indomethacin can reduce the antihypertensive effects of captopril and losartan. These interactions should be given consideration in patients taking NSAIDs concomitantly with ACE inhibitors or angiotensin II antagonists. In some patients with compromised renal function, the coadministration of an NSAID and an ACE inhibitor or an angiotensin II antagonist may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible.AspirinWhen indomethacin is administered with aspirin, its protein binding is reduced, although the clearance of free indomethacin is not altered. The clinical significance of this interaction is not known.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. In clinical study of the combined use of indomethacin and aspirin, the incidence of gastrointestinal side effects was significantly increased with combined therapy.In study in normal volunteers, it was found that chronic concurrent administration of3.6 of aspirin per day decreases indomethacin blood levels approximately 20%.Beta-Adrenoceptor Blocking AgentsBlunting of the antihypertensive effect of beta-adrenoceptor blocking agents by non-steroidal anti-inflammatory drugs including indomethacin has been reported. Therefore, when using these blocking agents to treat hypertension, patients should be observed carefully in order to confirm that the desired therapeutic effect has been obtained.CyclosporinAdministration of non-steroidal anti-inflammatory drugs concomitantly with cyclosporine has been associated with an increase in cyclosporine-induced toxicity, possibly due to decreased synthesis of renal prostacyclin. NSAIDs should be used with caution in patients taking cyclosporine, and renal function should be carefully monitored.DiflunisalIn normal volunteers receiving indomethacin, the administration of diflunisal decreased the renal clearance and significantly increased the plasma levels of indomethacin. In some patients, combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage. Therefore, diflunisal and indomethacin should not be used concomitantly.DigoxinIndomethacin given concomitantly with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Therefore, when indomethacin and digoxin are used concomitantly, serum digoxin levels should be closely monitored.DiureticsIn some patients, the administration of indomethacin can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing, and thiazide diuretics. This response has been attributed to inhibition of renal prostaglandin synthesis.Indomethacin reduces basal plasma renin activity (PRA), as well as those elevations of PRA induced by furosemide administration, or salt or volume depletion. These facts should be considered when evaluating plasma renin activity in hypertensive patients.It has been reported that the addition of triamterene to maintenance schedule of indomethacin resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin and triamterene should not be administered together.Indomethacin and potassium-sparing diuretics each may be associated with increased serum potassium levels. The potential effects of indomethacin and potassium-sparing diuretics on potassium kinetics and renal function should be considered when these agents are administered concurrently. Most of the above effects concerning diuretics have been attributed, at least in part, to mechanisms involving inhibition of prostaglandin synthesis by indomethacin.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.LithiumIndomethacin capsules 50 mg t.i.d. produced clinically relevant elevation of plasma lithium and reduction in renal lithium clearance in psychiatric patients and normal subjects with steady-state plasma lithium concentrations. This effect has been attributed to inhibition of prostaglandin synthesis. As consequence, when NSAIDs and lithium are given concomitantly, the patient should be carefully observed for signs of lithium toxicity. (Read circulars for lithium preparations before use of such concomitant therapy.) In addition, the frequency of monitoring serum lithium concentration should be increased at the outset of such combination drug treatment.MethotrexateNSAIDs 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.NSAIDsThe concomitant use of indomethacin with other NSAIDs is not recommended due to the increased possibility of gastrointestinal toxicity, with little or no increase in efficacy.Oral anticoagulantsClinical studies have shown that indomethacin does not influence the hypoprothrombinemia produced by anticoagulants. However, when any additional drug, including indomethacin, is added to the treatment of patients on anticoagulant therapy, the patients should be observed for alterations of the prothrombin time. In post-marketing experience, bleeding has been reported in patients on concomitant treatment with anticoagulants and indomethacin. Caution should be exercised when indomethacin and anticoagulants are administered concomitantly. The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have risk of serious GI bleeding higher than users of either drug alone.ProbenecidWhen indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased. Therefore, lower total daily dosage of indomethacin may produce satisfactory therapeutic effect. When increases in the dose of indomethacin are made, they should be made carefully and in small increments.. Drug/Laboratory Test Interactions. False-negative results in the dexamethasone suppression test (DST) in patients being treated with indomethacin have been reported. Thus, results of the DST should be interpreted with caution in these patients.. Carcinogenesis, Mutagenesis, Impairment of Fertility. In an 81-week chronic oral toxicity study in the rat at doses up to mg/kg/day, indomethacin had no tumorigenic effect.Indomethacin produced no neoplastic or hyperplastic changes related to treatment in carcinogenic studies in the rat (dosing period 73 to 110 weeks) and the mouse (dosing period 62 to 88 weeks) at doses up to 1.5 mg/kg/day.Indomethacin did not have any mutagenic effect in in vitro bacterial tests (Ames test and E. coli with or without metabolic activation) and series of in vivo tests including the host-mediated assay, sex-linked recessive lethals in Drosophila, and the micronucleus test in mice.Indomethacin at dosage levels up to 0.5 mg/kg/day had no effect on fertility in mice in two generation reproduction study or two litter reproduction study in rats.. Pregnancy. Teratogenic Effects. Pregnancy Category CTeratogenic studies were conducted in mice and rats at dosages of 0.5, 1, 2, and mg/kg/day. Except for retarded fetal ossification at mg/kg/day considered secondary to the decreased average fetal weights, no increase in fetal malformations was observed as compared with control groups. Other studies in mice reported in the literature using higher doses (5 to 15 mg/kg/day) have described maternal toxicity and death, increased fetal resorptions, and fetal malformations. Comparable studies in rodents using high doses of aspirin have shown similar maternal and fetal effects. However, animal reproduction studies are not always predictive of human response. There are no adequate and well controlled studies in pregnant women.Indomethacin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetusNonteratogenic EffectsBecause of the known effects of non-steroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided.The known effects of indomethacin and other drugs of this class on the human fetus during the third trimester of pregnancy include: constriction of the ductus arteriosus prenatally, tricuspid incompetence, and pulmonary hypertension; nonclosure of the ductus arteriosus postnatally which may be resistant to medical management; myocardial degenerative changes, platelet dysfunction with resultant bleeding, intracranial bleeding, renal dysfunction or failure, renal injury/dysgenesis which may result in prolonged or permanent renal failure, oligohydramnios, gastrointestinal bleeding or perforation, and increased risk of necrotizing enterocolitis.In rats and mice, mg/kg/day given during the last days of gestation caused decrease in maternal weight gain and some maternal and fetal deaths. An increased incidence of neuronal necrosis in the diencephalon in the live born fetuses was observed. At mg/kg/day, no increase in neuronal necrosis was observed as compared to the control groups. Administration of 0.5 or mg/kg/day during the first days of life did not cause an increase in neuronal necrosis at either dose level.. 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 on labor and delivery in pregnant women are unknown.. Nursing Mothers. Indomethacin is excreted in the milk of lactating mothers. Indomethacin is not recommended for use in nursing mothers.. Pediatric Use. Safety and effectiveness in pediatric patients 14 years of age and younger have not been established.Indomethacin should not be prescribed for pediatric patients 14 years of age and younger unless toxicity or lack of efficacy associated with other drugs warrants the risk.In experience with more than 900 pediatric patients reported in the literature or to the manufacturer who were treated with indomethacin capsules, side effects in pediatric patients were comparable to those reported in adults. Experience in pediatric patients has been confined to the use of indomethacin capsules.If decision is made to use indomethacin for pediatric patients years of age or older, such patients should be monitored closely and periodic assessment of liver function is recommended. There have been cases of hepatotoxicity reported in pediatric patients with juvenile rheumatoid arthritis, including fatalities. If indomethacin treatment is instituted, suggested starting dose is to mg/kg/day given in divided doses. Maximum daily dosage should not exceed mg/kg/day or 150 to 200 mg/day, whichever is less. Limited data are available to support the use of maximum daily dosage of mg/kg/day or 150 to 200 mg/day, whichever is less. As symptoms subside, the total daily dosage should be reduced to the lowest level required to control symptoms, or the drug should be discontinued.. Geriatric Use. As with any NSAID, caution should be exercised in treating the elderly (65 years and older) since advancing age appears to increase the possibility of adverse reactions (see WARNINGS, Gastrointestinal Effects: Risk of Ulceration, Bleeding, and Perforation and DOSAGE AND ADMINISTRATION). Elderly patients seem to tolerate ulceration or bleeding less well than other individuals and many spontaneous reports of fatal GI events are in this population (see WARNINGS: Gastrointestinal Effects: Risk of Ulceration, Bleeding, and Perforation).Indomethacin may cause confusion or, rarely, psychosis (see ADVERSE REACTIONS); physicians should remain alert to the possibility of such adverse effects in the elderly.This drug is known to be substantially excreted by the kidney and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to monitor renal function (see WARNINGS: Renal Effects).

SPL MEDGUIDE SECTION.

INDOMETHACIN CAPSULES USPMedication Guide for Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)(See the end of this Medication Guide for list of prescription NSAID medicines.) What is the most important information should know about medicines called Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) NSAID medicines may increase the chance of heart attack or stroke that can lead to death. This chance increases:with longer use of NSAID medicinesin people who have heart diseaseNSAID medicines should never be used right before or after heart surgery called coronary artery bypass graft (CABG). NSAID medicines can cause ulcers and bleeding in the stomach and intestines at any time during treatment. Ulcers and bleeding:can happen without warning symptomsmay cause deathThe chance of person getting an ulcer or bleeding increases with: taking medicines called corticosteroids and anticoagulantslonger usesmokingdrinking alcohololder agehaving poor healthNSAID medicines should only be used: exactly as prescribedat the lowest dose possible for your treatmentfor the shortest time neededWhat are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) NSAID medicines are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as:different types of arthritismenstrual cramps and other types of short-term painWho should not take Non-Steroidal Anti-Inflammatory Drug (NSAID) Do not take an NSAID medicine: if you had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAID medicinefor pain right before or after heart bypass surgeryTell your healthcare provider: about all of your medical conditions.about all of the medicines you take. NSAIDs and some other medicines can interact with each other and cause serious side effects. Keep list of your medicines to show to your healthcare provider and pharmacist. if you are pregnant. NSAID medicines should not be used by pregnant women late in their pregnancy. if you are breastfeeding. Talk to your doctor. What are the possible side effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) serious side effects include: Other side effects include: heart attackstrokehigh blood pressureheart failure from body swelling (fluid Retension)kidney problems including kidney failurebleeding and ulcers in the stomach and intestinelow red blood cells (anemia)life-threatening skin reactionslife-threatening allergic reactionsliver problems including liver failureasthma attacks in people who have asthmastomach painconstipationdiarrheagasheartburnnauseavomitingdizzinessGet emergency help right away if you have any of the following symptoms: shortness of breath or trouble breathingchest painweakness in one part or side of your bodyslurred speechswelling of the face or throatStop your NSAID medicine and call your healthcare provider right away if you have any of the following symptoms: nauseamore tired or weaker than usualitchingyour skin or eyes look yellowstomach painflu-like symptomsvomit bloodthere is blood in your bowel movement or it is black and sticky like tarunusual weight gainskin rash or blisters with feverswelling of the arms and legs, hands and feetThese are not all the side effects with NSAID medicines. Talk to your healthcare provider or pharmacist for more information about NSAID medicines. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Other information about Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Aspirin is an NSAID medicine but it does not increase the chance of heart attack.Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines.Some of these NSAID medicines are sold in lower doses without prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days.NSAID medicines that need prescriptionCelecoxib CelebrexDiclofenac Cataflam, Voltaren, Arthrotec (combined with misoprostol)Diflunisal DolobidEtodolac Lodine, Lodine XLFenoprofen Nalfon, Nalfon 200Flurbiprofen AnsaidIbuprofen Motrin, Tab-Profen, Vicoprofen( (combined with hydrocodone), Combunox (combined with oxycodone)Indomethacin Indocin, Indocin SR, Indo-Lemmon, IndomethaganKetoprofen OruvailKetorolac ToradolMefenamicAcid PonstelMeloxicam MobicNabumetone RelafenNaproxen Naprosyn, Anaprox, Anaprox DS, EC-Naprosyn, Naprelan, Naprapac (copackaged with lansoprazole)Oxaprozin DayproPiroxicam FeldeneSulindac ClinorilTolmetin Tolectin, Tolectin DS, Tolectin 600Vicoprofen contains the same dose of ibuprofen as over-the-counter (OTC) NSAIDs, and is usually used for less than 10 days to treat pain. The OTC NSAIDS label warns that long term continuous use may increase the risk of heart attack or stroke.This Medication Guide has been approved by the U.S. Food and Drug Administration. Manufactured for:Camber Pharmaceuticals, IncPiscataway, NJ 08854By: Hetero Labs LimitedJeedimetla, Hyderabad-500 055, India.. with longer use of NSAID medicines. in people who have heart disease. can happen without warning symptoms. may cause death. taking medicines called corticosteroids and anticoagulants. longer use. smoking. drinking alcohol. older age. having poor health. exactly as prescribed. at the lowest dose possible for your treatment. for the shortest time needed. different types of arthritis. menstrual cramps and other types of short-term pain. if you had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAID medicine. for pain right before or after heart bypass surgery. about all of your medical conditions.. about all of the medicines you take. NSAIDs and some other medicines can interact with each other and cause serious side effects. Keep list of your medicines to show to your healthcare provider and pharmacist. if you are pregnant. NSAID medicines should not be used by pregnant women late in their pregnancy. if you are breastfeeding. Talk to your doctor. heart attack. stroke. high blood pressure. heart failure from body swelling (fluid Retension). kidney problems including kidney failure. bleeding and ulcers in the stomach and intestine. low red blood cells (anemia). life-threatening skin reactions. life-threatening allergic reactions. liver problems including liver failure. asthma attacks in people who have asthma. stomach pain. constipation. diarrhea. gas. heartburn. nausea. vomiting. dizziness. shortness of breath or trouble breathing. chest pain. weakness in one part or side of your body. slurred speech. swelling of the face or throat. nausea. more tired or weaker than usual. itching. your skin or eyes look yellow. stomach pain. flu-like symptoms. vomit blood. there is blood in your bowel movement or it is black and sticky like tar. unusual weight gain. skin rash or blisters with fever. swelling of the arms and legs, hands and feet.

WARNINGS SECTION.

WARNINGS. Cardiovascular Effects. Cardiovascular Thrombotic EventsClinical trials of several COX-2 selective and nonselective NSAIDs of up to 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 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 an 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 an NSAID does increase the risk of serious GI events (see WARNINGS: Gastrointestinal Effects).Two large, controlled, clinical trials of COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see CONTRAINDICATIONS).HypertensionNSAIDs, including indomethacin, 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, 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 EdemaFluid retention and edema have been observed in some patients taking NSAIDs. Indomethacin should be used with caution in patients with fluid retention or heart failure.In study of patients with severe heart failure and hyponatremia, indomethacin was associated with significant deterioration of circulatory hemodynamics, presumably due to inhibition of prostaglandin dependent compensatory mechanisms.. Gastrointestinal Effects. Risk of Ulceration, Bleeding, and Perforation. NSAIDs, including indomethacin, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, 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 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 to months, and in about to 4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk.Rarely, in patients taking indomethacin, intestinal ulceration has been associated with stenosis and obstruction. Gastrointestinal bleeding without obvious ulcer formation and perforation of preexisting sigmoid lesions (diverticulum, carcinoma, etc.) have occurred. Increased abdominal pain in ulcerative colitis patients or the development of ulcerative colitis and regional ileitis have been reported to occur rarely.NSAIDs should be prescribed with extreme caution in those with prior history of ulcer disease or gastrointestinal bleeding. Patients with prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have greater than 10-fold increased risk for developing 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 an 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 serious GI adverse event is suspected. This should include discontinuation of the NSAID until 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 compensatory role in the maintenance of renal perfusion. In these patients, administration of non-steroidal anti-inflammatory drug may cause dose dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate over renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, patients with volume depletion, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.Increases in serum potassium concentration, including hyperkalemia, have been reported with use of indomethacin, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to hyporeninemic-hypoaldosteronism state (see PRECAUTIONS: Drug Interactions).Advanced Renal DiseaseNo information is available from controlled clinical studies regarding the use of indomethacin in patients with advanced renal disease. Therefore, treatment with indomethacin is not recommended in these patients with advanced renal disease. If indomethacin therapy must be initiated, close monitoring of the patients renal function is advisable.. Anaphylactic/Anaphylactoid Reactions. As with other NSAIDs, anaphylactic/anaphylactoid reactions may occur in patients without known prior exposure to indomethacin. Indomethacin 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: General: Preexisting Asthma). Emergency help should be sought in cases where an anaphylactic/anaphylactoid reaction occurs.Skin ReactionsNSAIDs, including indomethacin, 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.PregnancyIn late pregnancy, as with other NSAIDs, indomethacin should be avoided because it may cause premature closure of the ductus arteriosus.Ocular EffectsCorneal deposits and retinal disturbances, including those of the macula, have been observed in some patients who had received prolonged therapy with indomethacin. The prescribing physician should be alert to the possible association between the changes noted and indomethacin. It is advisable to discontinue therapy if such changes are observed. Blurred vision may be significant symptom and warrants thorough ophthalmological examination. Since these changes may be asymptomatic, ophthalmologic examination at periodic intervals is desirable in patients where therapy is prolonged.Central Nervous System EffectsIndomethacin may aggravate depression or other psychiatric disturbances, epilepsy, and parkinsonism, and should be used with considerable caution in patients with these conditions. If severe CNS adverse reactions develop, indomethacin should be discontinued.Indomethacin may cause drowsiness; therefore, patients should be cautioned about engaging in activities requiring mental alertness and motor coordination, such as driving car. Indomethacin may also cause headache. Headache which persists despite dosage reduction requires cessation of therapy with indomethacin.

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential. InfertilityFemales Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including indomethacin, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown reversible delay in ovulation. Consider withdrawal of NSAIDs, including indomethacin, in women who have difficulties conceiving or who are undergoing investigation of infertility.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis Mutagenesis Impairment Of Fertility. Carcinogenesis In an 81-week chronic oral toxicity study in the rat at doses up to mg/kg/day (0.05 times the [MRHD] on mg/m2 basis), indomethacin had no tumorigenic effect. Indomethacin produced no neoplastic or hyperplastic changes related to treatment in carcinogenic studies in the rat (dosing period 73 to 110 weeks) and the mouse (dosing period 62 to 88 weeks) at doses up to 1.5 mg/kg/day (0.04 times [mice] and 0.07 times [rats] the MRHD on mg/m2 basis, respectively). Mutagenesis Indomethacin did not have any mutagenic effect in in vitro bacterial tests and series of in vivo tests including the host-mediated assay, sex-linked recessive lethal in Drosophila, and the micronucleus test in mice. Impairment of Fertility Indomethacin at dosage levels up to 0.5 mg/kg/day had no effect on fertility in mice in two generation reproduction study (0.01 times the MRHD on mg/m2 basis) or two litter reproduction study in rats (0.02 times the MRHD on mg/m2 basis).

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 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 reduction in joint swelling, average number of joints involved, and morning stiffness; by increased mobility as demonstrated by decrease in walking time; and by improved functional capability as demonstrated by an increase in grip strength. Indomethacin may enable the reduction of steroid dosage in patients receiving steroids for the more severe forms of rheumatoid arthritis. In such instances the steroid dosage should be reduced slowly and the patients followed very closely for any possible adverse effects.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS STRENGTHS. Indomethacin capsules USP, 25 mg are size hard gelatin capsules, with opaque light green cap imprinted with and opaque light green body imprinted with 103, containing white to off-white powder. Indomethacin capsules USP, 50 mg are size hard gelatin capsules, with opaque light green cap imprinted with and opaque light green body imprinted with 104, containing white to off-white powder.. Indomethacin Capsules: 25 mg and 50 mg (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. See Table for clinically significant drug interactions with indomethacin. Table 2: Clinically Significant Drug Interactions with Indomethacin Drugs That Interfere with Hemostasis Clinical Impact:Indomethacin and anticoagulants such as warfarin have synergistic effect on bleeding. The concomitant use of indomethacin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of indomethacin with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.11)]. AspirinClinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In clinical study, the concomitant use of an NSAID and aspirin was associated with significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)]. Intervention Concomitant use of indomethacin and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.11)]. Indomethacin capsule is not substitute for low dose aspirin for cardiovascular protection. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: During concomitant use of indomethacin and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.During concomitant use of indomethacin and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis.It has been reported that the addition of triamterene to maintenance schedule of indomethacin resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin and triamterene should not be administered together. Both indomethacin capsules and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently. Intervention: Indomethacin and triamterene should not be administered together. During concomitant use of indomethacin capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. Be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels [see Warnings and Precautions (5.6)]. Digoxin Clinical Impact: The concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of indomethacin capsules and digoxin, monitor serum digoxin levels. LithiumClinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of indomethacin capsules and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of indomethacin capsules and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of indomethacin and cyclosporine may increase cyclosporines nephrotoxicity. Intervention: During concomitant use of indomethacin and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of indomethacin with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)]. Combined use with diflunisal may be particularly hazardous because diflunisal causes significantly higher plasma levels of indomethacin. [see Clinical Pharmacology (12.3)]. In some patients, combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage. Intervention: The concomitant use of indomethacin with other NSAIDs or salicylates, especially diflunisal, is not recommended. Pemetrexed Clinical Impact: Concomitant use of indomethacin and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of indomethacin and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. ProbenecidClinical Impact: When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased. Intervention: During the concomitant use of indomethacin and probenecid, lower total daily dosage of indomethacin may produce satisfactory therapeutic effect. When increases in the dose of indomethacin are made, they should be made carefully and in small increments. Effects on Laboratory Tests Indomethacin reduces basal plasma renin activity (PRA), as well as those elevations of PRA induced by furosemide administration, or salt or volume depletion. These facts should be considered when evaluating plasma renin activity in hypertensive patients. False-negative results in the dexamethasone suppression test (DST) in patients being treated with indomethacin have been reported. Thus, results of the DST should be interpreted with caution in these patients.. Indomethacin and anticoagulants such as warfarin have synergistic effect on bleeding. The concomitant use of indomethacin and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. During concomitant use of indomethacin and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained.. During concomitant use of indomethacin and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. o Drugs that Interfere with Hemostasis (e.g. warfarin, aspirin, SSRIs/SNRIs): Monitor patients for bleeding who are concomitantly taking indomethacin with drugs that interfere with hemostasis. Concomitant use of indomethacin and analgesic doses of aspirin is not generally recommended (7) ACE Inhibitors, Angiotensin Receptor Blockers (ARB), or Beta-Blockers: Concomitant use with indomethacin may diminish the antihypertensive effect of these drugs. Monitor blood pressure (7) ACE Inhibitors and ARBs: Concomitant use with indomethacin in elderly, volume depleted, or those with renal impairment may result in deterioration of renal function. In such high risk patients, monitor for signs of worsening renal function (7) Diuretics: NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects (7) Digoxin: Concomitant use with indomethacin can increase serum concentration and prolong half-life of digoxin. Monitor serum digoxin levels (7).

GERIATRIC USE SECTION.

8.5 Geriatric Use. Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.13)]. Indomethacin may cause confusion or, rarely, psychosis [see Adverse Reaction (6.1)]; physicians should remain alert to the possibility of such adverse effects in the elderly Indomethacin and its metabolites are known to be substantially excreted by the kidneys, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, use caution in this patient population, and it may be useful to monitor renal function [see Clinical Pharmacology (12.3)].

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with indomethacin capsules and periodically during the course of ongoing therapy. Cardiovascular Thrombotic Events Advice 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 and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions (5.2)]. Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and flu-like symptoms). If these occur, instruct patients to stop indomethacin capsules and seek immediate medical therapy [see Warnings and Precautions (5.3)]. Heart Failure and Edema Advice 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 and Precautions (5.5 )]. Anaphylactic Reactions Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications (4) and Warnings and Precautions (5.7)]. Serious Skin Reactions Advice patients to stop indomethacin capsules immediately if they develop any type of rash and to contact their healthcare provider as soon as possible [see Warnings and Precautions (5.9)]. Female Fertility Advise females of reproductive potential who desire pregnancy that NSAIDs, including indomethacin, may be associated with reversible delay in ovulation [see Use in Specific Populations (8.3)]. Fetal Toxicity Inform pregnant women to avoid use of indomethacin capsules and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductusarteriosus [see Warnings and Precautions (5.10) and Use in Specific Populations (8.1)]. Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of indomethacin capsules with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2) and Drug Interactions (7)]. Alert patients that NSAIDs may be present in over the counter medications for treatment of colds, fever, or insomnia. Use of NSAIDS and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with indomethacin capsules until they talk to their healthcare provider [see Drug Interactions (7)]. Manufactured for: Camber Pharmaceuticals, Inc. Piscataway, NJ 08854 By: HETEROTM HETERO LABS LIMITED Jeedimetla, Hyderabad 500 055, India. Revised: November/2017. indomethacincamberlogo1.

LACTATION SECTION.

8.2 Lactation. Risk Summary Based on available published clinical data, indomethacin may be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for indomethacin and any potential adverse effects on the breastfed infant from the indomethacin or from the underlying maternal condition. Data In one study, levels of indomethacin in breast milk were below the sensitivity of the assay (<20 mcg/L) in 11 of 15 women using doses ranging from 75 mg orally to 300 mg rectally daily (0.94 to 4.29 mg/kg daily) in the postpartum period. Based on these levels, the average concentration present in breast milk was estimated to be 0.27% of the maternal weight-adjusted dose. In another study indomethacin levels were measured in breast milk of eight postpartum women using doses of 75 mg daily and the results were used to calculate an estimated infant daily dose. The estimated infant dose of indomethacin from breast milk was less than 30 mcg/day or 4.5 mcg/kg/day assuming breast milk intake of 150 mL/kg/day. This is 0.5% of the maternal weight-adjusted dosage or about 3% of the neonatal dose for treatment of patent ductus arteriosus.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Indomethacin has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of indomethacin capsules, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Indomethacin is potent inhibitor of prostaglandin synthesis in vitro. Indomethacin concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because indomethacin is an inhibitor of prostaglandin synthesis, its mode of action may be due to decrease of prostaglandins in peripheral tissues.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis Mutagenesis Impairment Of Fertility. Carcinogenesis In an 81-week chronic oral toxicity study in the rat at doses up to mg/kg/day (0.05 times the [MRHD] on mg/m2 basis), indomethacin had no tumorigenic effect. Indomethacin produced no neoplastic or hyperplastic changes related to treatment in carcinogenic studies in the rat (dosing period 73 to 110 weeks) and the mouse (dosing period 62 to 88 weeks) at doses up to 1.5 mg/kg/day (0.04 times [mice] and 0.07 times [rats] the MRHD on mg/m2 basis, respectively). Mutagenesis Indomethacin did not have any mutagenic effect in in vitro bacterial tests and series of in vivo tests including the host-mediated assay, sex-linked recessive lethal in Drosophila, and the micronucleus test in mice. Impairment of Fertility Indomethacin at dosage levels up to 0.5 mg/kg/day had no effect on fertility in mice in two generation reproduction study (0.01 times the MRHD on mg/m2 basis) or two litter reproduction study in rats (0.02 times the MRHD on mg/m2 basis).

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Safety and effectiveness in pediatric patients 14 years of age and younger has not been established. Indomethacin capsules should not be prescribed for pediatric patients 14 years of age and younger unless toxicity or lack of efficacy associated with other drugs warrants the risk. In experience with more than 900 pediatric patients reported in the literature or to the manufacturer who were treated with indomethacin capsules, side effects in pediatric patients were comparable to those reported in adults. Experience in pediatric patients has been confined to the use of indomethacin capsules. If decision is made to use indomethacin for pediatric patients two years of age or older, such patients should be monitored closely and periodic assessment of liver function is recommended. There have been cases of hepatotoxicity reported in pediatric patients with juvenile rheumatoid arthritis, including fatalities. If indomethacin treatment is instituted, suggested starting dose is to mg/kg/day given in divided doses. Maximum daily dosage should not exceed mg/kg/day or 150 to 200 mg/day, whichever is less. Limited data are available to support the use of maximum daily dosage of mg/kg/day or 150 to 200 mg/day, whichever is less. As symptoms subside, the total daily dosage should be reduced to the lowest level required to control symptoms, or the drug should be discontinued.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Absorption Following single oral doses of indomethacin capsules 25 mg or 50 mg, indomethacin is readily absorbed, attaining peak plasma concentrations of about and mcg/mL, respectively, at about hours. Orally administered indomethacin capsules are virtually 100% bioavailable, with 90% of the dose absorbed within hours. single 50 mg dose of indomethacin oral suspension was found to be bioequivalent to 50 mg indomethacin capsule when each was administered with food. With typical therapeutic regimen of 25 mg or 50 mg three times day, the steady-state plasma concentrations of indomethacin are an average 1.4 times those following the first dose. Distribution Indomethacin is highly bound to protein in plasma (about 99%) over the expected range of therapeutic plasma concentrations. Indomethacin has been found to cross the blood-brain barrier and the placenta, and appears in breast milk. Elimination Metabolism: Indomethacin exists in the plasma as the parent drug and its desmethyl, desbenzoyl, and desmethyldesbenzoyl metabolites, all in the unconjugated form. Appreciable formation of glucuronide conjugates of each metabolite and of indomethacin are formed. Excretion Indomethacin is eliminated via renal excretion, metabolism, and biliary excretion. Indomethacin undergoes appreciable enterohepatic circulation. About 60% of an oral dose is recovered in urine as drug and metabolites (26% as indomethacin and its glucuronide), and 33% is recovered in feces (1.5% as indomethacin). The mean half-life of indomethacin is estimated to be about 4.5 hours. Specific Populations Pediatric: The pharmacokinetics of indomethacin has not been investigated in pediatric patients. Race: Pharmacokinetic differences due to race have not been identified. Hepatic Impairment: The pharmacokinetics of indomethacin has not been investigated in patients with hepatic impairment. Renal Impairment: The pharmacokinetics of indomethacin has not been investigated in patients with renal impairment [see Warnings and Precautions (5.6)]. Drug Interaction Studies Aspirin: In study in normal volunteers, it was found that chronic concurrent administration of 3.6 of aspirin per day decreases indomethacin blood levels approximately 20% [see Drug Interactions (7)]. When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table for clinically significant drug interactions of NSAIDs with aspirin [see Drug Interactions (7)]. Diflunisal: In normal volunteers receiving indomethacin, the administration of diflunisal decreased the renal clearance and significantly increased the plasma levels of indomethacin [see Drug Interactions(7)].

PREGNANCY SECTION.

8.1 Pregnancy. Risk Summary Use of NSAIDs, including indomethacin capsules, during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including indomethacin, in pregnant women starting at 30 weeks of gestation (third trimester). There are no adequate and well-controlled studies of indomethacin capsules in pregnant women. Data from observational studies regarding potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In the general U.S. population, all clinically recognized pregnancies, regardless of drug exposure, have background rate of to 4% for major malformations, and 15 to 20% for pregnancy loss. In animal reproduction studies retarded fetal ossification was observed with administration of indomethacin to mice and rats during organogenesis at doses 0.1 and 0.2 times, respectively, the maximum recommended human dose (MRHD, 200 mg). In published studies in pregnant mice, indomethacin produced maternal toxicity and death, increased fetal resorptions, and fetal malformations at 0.1 times the MRHD. When rat and mice dams were dosed during the last three days of gestation, indomethacin produced neuronal necrosis in the offspring at 0.1 and 0.05 times the MRHD, respectively [see Data]. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as indomethacin, resulted in increased pre- and post-implantation loss. Clinical Considerations Labor or Delivery There are no studies on the effects of indomethacin during labor or delivery. In animal studies, NSAIDS, including indomethacin, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data Animal data Reproductive studies were conducted in mice and rats at dosages of 0.5, 1.0, 2.0, and 4.0 mg/kg/day. Except for retarded fetal ossification at mg/kg/day (0.1 times [mice] and 0.2 times [rats] the MRHD on mg/m2 basis, respectively) considered secondary to the decreased average fetal weights, no increase in fetal malformations was observed as compared with control groups. Other studies in mice reported in the literature using higher doses (5 to 15 mg/kg/day, 0.1 to 0.4 times MRHD on mg/m2 basis) have described maternal toxicity and death, increased fetal resorptions, and fetal malformations. In rats and mice, maternal indomethacin administration of 4.0 mg/kg/day (0.2 times and 0.1 times the MRHD on mg/m2 basis) during the last days of gestation was associated with an increased incidence of neuronal necrosis in the diencephalon in the live-born fetuses, however no increase in neuronal necrosis was observed at mg/kg/day as compared to the control groups (0.1 times and 0.05 times the MRHD on mg/m2 basis). Administration of 0.5 or 4.0 mg/kg/day to offspring during the first days of life did not cause an increase in neuronal necrosis at either dose level.

RECENT MAJOR CHANGES SECTION.

Boxed Warning 05/2016 Warnings and Precautions, Cardiovascular Thrombotic Events (5.1) 05/2016 Warnings and Precautions, Heart Failure and Edema (5.5) 05/2016.

SPL UNCLASSIFIED SECTION.

2.1 General Dosing Instructions. Carefully consider the potential benefits and risks of indomethacin capsules and other treatment options before deciding to use indomethacin capsules. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5)]. After observing the response to initial therapy with indomethacin, the dose and frequency should be adjusted to suit an individual patients needs. Adverse reactions generally appear to correlate with the dose of indomethacin. Therefore, every effort should be made to determine the lowest effective dosage for the individual patient. Dosage recommendations for active stages of the following:.

STORAGE AND HANDLING SECTION.

Storage. Store at 20 to 25C (68 to 77F) [see USP Controlled Room Temperature].Protect from light.Dispense in tight, light-resistant container as defined in the USP using child-resistant closure.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy: Use of NSAIDs during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs in pregnant women starting at 30 weeks gestation (5.10, 8)Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal of indomethacin capsules in women who have difficulties conceiving (8.3). 8.1 Pregnancy. Risk Summary Use of NSAIDs, including indomethacin capsules, during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including indomethacin, in pregnant women starting at 30 weeks of gestation (third trimester). There are no adequate and well-controlled studies of indomethacin capsules in pregnant women. Data from observational studies regarding potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In the general U.S. population, all clinically recognized pregnancies, regardless of drug exposure, have background rate of to 4% for major malformations, and 15 to 20% for pregnancy loss. In animal reproduction studies retarded fetal ossification was observed with administration of indomethacin to mice and rats during organogenesis at doses 0.1 and 0.2 times, respectively, the maximum recommended human dose (MRHD, 200 mg). In published studies in pregnant mice, indomethacin produced maternal toxicity and death, increased fetal resorptions, and fetal malformations at 0.1 times the MRHD. When rat and mice dams were dosed during the last three days of gestation, indomethacin produced neuronal necrosis in the offspring at 0.1 and 0.05 times the MRHD, respectively [see Data]. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as indomethacin, resulted in increased pre- and post-implantation loss. Clinical Considerations Labor or Delivery There are no studies on the effects of indomethacin during labor or delivery. In animal studies, NSAIDS, including indomethacin, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data Animal data Reproductive studies were conducted in mice and rats at dosages of 0.5, 1.0, 2.0, and 4.0 mg/kg/day. Except for retarded fetal ossification at mg/kg/day (0.1 times [mice] and 0.2 times [rats] the MRHD on mg/m2 basis, respectively) considered secondary to the decreased average fetal weights, no increase in fetal malformations was observed as compared with control groups. Other studies in mice reported in the literature using higher doses (5 to 15 mg/kg/day, 0.1 to 0.4 times MRHD on mg/m2 basis) have described maternal toxicity and death, increased fetal resorptions, and fetal malformations. In rats and mice, maternal indomethacin administration of 4.0 mg/kg/day (0.2 times and 0.1 times the MRHD on mg/m2 basis) during the last days of gestation was associated with an increased incidence of neuronal necrosis in the diencephalon in the live-born fetuses, however no increase in neuronal necrosis was observed at mg/kg/day as compared to the control groups (0.1 times and 0.05 times the MRHD on mg/m2 basis). Administration of 0.5 or 4.0 mg/kg/day to offspring during the first days of life did not cause an increase in neuronal necrosis at either dose level.. 8.2 Lactation. Risk Summary Based on available published clinical data, indomethacin may be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for indomethacin and any potential adverse effects on the breastfed infant from the indomethacin or from the underlying maternal condition. Data In one study, levels of indomethacin in breast milk were below the sensitivity of the assay (<20 mcg/L) in 11 of 15 women using doses ranging from 75 mg orally to 300 mg rectally daily (0.94 to 4.29 mg/kg daily) in the postpartum period. Based on these levels, the average concentration present in breast milk was estimated to be 0.27% of the maternal weight-adjusted dose. In another study indomethacin levels were measured in breast milk of eight postpartum women using doses of 75 mg daily and the results were used to calculate an estimated infant daily dose. The estimated infant dose of indomethacin from breast milk was less than 30 mcg/day or 4.5 mcg/kg/day assuming breast milk intake of 150 mL/kg/day. This is 0.5% of the maternal weight-adjusted dosage or about 3% of the neonatal dose for treatment of patent ductus arteriosus.. 8.3 Females and Males of Reproductive Potential. InfertilityFemales Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including indomethacin, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown reversible delay in ovulation. Consider withdrawal of NSAIDs, including indomethacin, in women who have difficulties conceiving or who are undergoing investigation of infertility.. 8.4 Pediatric Use. Safety and effectiveness in pediatric patients 14 years of age and younger has not been established. Indomethacin capsules should not be prescribed for pediatric patients 14 years of age and younger unless toxicity or lack of efficacy associated with other drugs warrants the risk. In experience with more than 900 pediatric patients reported in the literature or to the manufacturer who were treated with indomethacin capsules, side effects in pediatric patients were comparable to those reported in adults. Experience in pediatric patients has been confined to the use of indomethacin capsules. If decision is made to use indomethacin for pediatric patients two years of age or older, such patients should be monitored closely and periodic assessment of liver function is recommended. There have been cases of hepatotoxicity reported in pediatric patients with juvenile rheumatoid arthritis, including fatalities. If indomethacin treatment is instituted, suggested starting dose is to mg/kg/day given in divided doses. Maximum daily dosage should not exceed mg/kg/day or 150 to 200 mg/day, whichever is less. Limited data are available to support the use of maximum daily dosage of mg/kg/day or 150 to 200 mg/day, whichever is less. As symptoms subside, the total daily dosage should be reduced to the lowest level required to control symptoms, or the drug should be discontinued.. 8.5 Geriatric Use. Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.13)]. Indomethacin may cause confusion or, rarely, psychosis [see Adverse Reaction (6.1)]; physicians should remain alert to the possibility of such adverse effects in the elderly Indomethacin and its metabolites are known to be substantially excreted by the kidneys, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, use caution in this patient population, and it may be useful to monitor renal function [see Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Hepatotoxicity: Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop (5.3) Hypertension: Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure (5.4, 7) Heart Failure and Edema: Avoid use of indomethacin in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure (5.5) Renal Toxicity: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of indomethacin in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function (5.6) Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs (5.7) Exacerbation of Asthma Related to Aspirin Sensitivity: Indomethacin is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity) (5.8) Serious Skin Reactions: Discontinue indomethacin at first appearance of skin rash or other signs of hypersensitivity (5.9) Premature Closure of Fetal Ductus Arteriosus: Avoid use in pregnant women starting at 30 weeks gestation (5.10, 8.1) Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia (5.11, 7). 5.1 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 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 and Precautions (5.2)]. Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled clinical trials of COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see Contraindications (4)]. 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 capsules in patients with recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If indomethacin capsules are used in patients with recent MI, monitor patients for signs of cardiac ischemia.. 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation. NSAIDs, including indomethacin, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, 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 serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for to months, and in about 2% to 4% of patients treated for one year. However, even short-term NSAID therapy is not without risk. Risk Factors for GI Bleeding, Ulceration, and Perforation Patients with prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had greater than 10-fold increased risk for developing GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding. Strategies to Minimize the GI Risks in NSAID-treated patients: Use the lowest effective dosage for the shortest possible duration. Avoid administration of more than one NSAID at time. Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs. Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy. If serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue indomethacin until serious GI adverse event is ruled out. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see Drug Interactions (7)].. 5.3 Hepatotoxicity. Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported. Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including indomethacin. Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and flu-like symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue indomethacin immediately, and perform clinical evaluation of the patient.. 5.4 Hypertension. NSAIDs, including indomethacin, can lead to new onset of hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)]. Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy.. 5.5 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 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 (7)]. Avoid the use of indomethacin in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If indomethacin capsules are used in patients with severe heart failure, monitor patients for signs of worsening heart failure.. 5.6 Renal Toxicity and Hyperkalemia. Renal Toxicity 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 compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause 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, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. No information is available from controlled clinical studies regarding the use of indomethacin in patients with advanced renal disease. The renal effects of indomethacin capsules may hasten the progression of renal dysfunction in patients with preexisting renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating indomethacin. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of indomethacin [see Drug Interactions (7)]. Avoid the use of indomethacin in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If indomethacin is used in patients with advanced renal disease, monitor patients for signs of worsening renal function. It has been reported that the addition of the potassium-sparing diuretic, triamterene, to maintenance schedule of indomethacin resulted in reversible acute renal failure in two of four healthy volunteers. Indomethacin and triamterene should not be administered together. Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to hyporeninemic-hypoaldosteronism state. Both indomethacin and potassium-sparing diuretics may be associated with increased serum potassium levels. The potential effects of indomethacin and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently.. 5.7 Anaphylactic Reactions. Indomethacin has been associated with anaphylactic reactions in patients with and without known hypersensitivity to indomethacin and in patients with aspirin-sensitive asthma [see Contraindications (4) and Warnings and Precautions (5.8)]. Seek emergency help if an anaphylactic reaction occurs.. 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity. subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, indomethacin is contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4)]. When indomethacin capsules are used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.. 5.9 Serious Skin Reactions. NSAIDs, including indomethacin, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of indomethacin at the first appearance of skin rash or any other sign of hypersensitivity. Indomethacin is contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)].. 5.10 Premature Closure of Fetal Ductus Arteriosus. Indomethacin may cause premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including indomethacin, in pregnant women starting at 30 weeks of gestation (third trimester) [see Use in Specific Populations (8.1)].. 5.11 Hematologic Toxicity. Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If patient treated with indomethacin has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including indomethacin, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)].. 5.12 Masking of Inflammation and Fever. The pharmacological activity of indomethacin in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.. 5.13 Laboratory Monitoring. Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with CBC and chemistry profile periodically [see Warnings and Precautions (5.2, 5.3, 5.6)].. 5.14 Central Nervous System Effects. Indomethacin may aggravate depression or other psychiatric disturbances, epilepsy, and parkinsonism, and should be used with considerable caution in patients with these conditions. Discontinue indomethacin capsules if severe CNS adverse reactions develop. Indomethacin may cause drowsiness; therefore, caution patients about engaging in activities requiring mental alertness and motor coordination, such as driving car. Indomethacin may also cause headache. Headache which persists despite dosage reduction requires cessation of therapy with indomethacin.. 5.15 Ocular Effects. Corneal deposits and retinal disturbances, including those of the macula, have been observed in some patients who had received prolonged therapy with indomethacin. Be alert to the possible association between the changes noted and indomethacin. It is advisable to discontinue therapy if such changes are observed. Blurred vision may be significant symptom and warrants thorough ophthalmological examination. Since these changes may be asymptomatic, ophthalmologic examination at periodic intervals is desirable in patients receiving prolonged therapy. Indomethacin is not indicated for long-term treatment.