Indomethacin

WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS Cardiovascular Thrombotic Events • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use [ see Warnings and Precautions ( 5.1 ) ]. • Indomethacin capsules are contraindicated in the setting of coronary artery bypass graft (CABG) surgery [ see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 ) ]. Gastrointestinal Bleeding, Ulceration, and Perforation • NSAIDs cause an increased risk of serious gastrointestinal (GI) 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 and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events [ see Warnings and Precautions ( 5.2 ) ]. See full prescribing information for complete boxed warning. • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use ( 5.1 ) • Indomethacin capsules are contraindicated in the setting of coronary artery bypass graft (CABG) surgery ( 4 , 5.1 ) • NSAIDs cause an increased risk of serious gastrointestinal (GI) 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 and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events (5.2 )

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 ) • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue and evaluate clinically ( 5.10 ). • Fetal Toxicity: Limit use of NSAIDs, including indomethacin, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal renal dysfunction and premature closure of the fetal ductus arteriosus ( 5.11 , 8.1 ). • Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia ( 5.12 , 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 a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as indomethacin, increases the risk of serious gastrointestinal (GI) events [ see Warnings and Precautions ( 5.2 ) ]. Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 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 a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If indomethacin capsules are used in patients with a 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 a 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 3 to 6 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 a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a 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 a 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 a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue indomethacin until a 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 a clinical evaluation of the patient. 5.4 Hypertension NSAIDs, including indomethacin, can lead to new onset of hypertension or worsening of preexisting 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 a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of indomethacin may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [ see Drug Interactions ( 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 a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, 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 a 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 a 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 A 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.NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant knownas generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. 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 capsules at the first appearance of skin rash or any other sign of hypersensitivity. Indomethacin capsules are contraindicated in patients with previous serious skin reactions to NSAIDs [ see Contraindications ( 4 ) ]. 5.10 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as indomethacin. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue indomethacin and evaluate the patient immediately. 5.11 Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDs, including indomethacin, in pregnant women at about 30 weeks gestation and later. NSAIDs, including indomethacin, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs, including indomethacin, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit indomethacin use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if indomethacin treatment extends beyond 48 hours. Discontinue indomethacin if oligohydramnios occurs and follow up according to clinical practice [ see Use in Specific Populations (8.1) ]. 5.12 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 a 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 ) ]. 5.13 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. 5.14 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 a CBC and a chemistry profile periodically [ see Warnings and Precautions ( 5.2 , 5.3 , 5.6 ) ]. 5.15 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 a car. Indomethacin may also cause headache. Headache which persists despite dosage reduction requires cessation of therapy with indomethacin. 5.16 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 a significant symptom and warrants a 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.

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Cardiovascular Thrombotic Events [ see Warnings and Precautions ( 5.1 ) ] • GI Bleeding, Ulceration and Perforation [ see Warnings and Precautions ( 5.2 ) ] • Hepatotoxicity [ see Warnings and Precautions ( 5.3 ) ] • Hypertension [ see Warnings and Precautions ( 5.4 ) ] • Heart Failure and Edema [ see Warnings and Precautions ( 5.5 ) ] • Renal Toxicity and Hyperkalemia [ see Warnings and Precautions ( 5.6 ) ] • Anaphylactic Reactions [ see Warnings and Precautions ( 5.7 ) ] • Serious Skin Reactions [ see Warnings and Precautions ( 5.9 ) ] • Hematologic Toxicity [ see Warnings and Precautions ( 5.12 ) ] Most common adverse reactions (incidence ≥ 3%) are headache, dizziness, dyspepsia and nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Hetero Labs Limited at 1-866-495-1995 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. In a gastroscopic study in 45 healthy subjects, the number of gastric mucosal abnormalities was significantly higher in the group receiving indomethacin capsules than in the group taking indomethacin suppositories or placebo. In a double-blind comparative clinical study involving 175 patients with rheumatoid arthritis, however, the incidence of upper gastrointestinal adverse effects with indomethacin capsules or suppositories was comparable. The incidence of lower gastrointestinal adverse effects was greater in the suppository group. The adverse reactions for indomethacin capsules listed in the following table have been arranged into two groups: (1) incidence greater than 1%; and (2) incidence less than 1%. The incidence for group (1) was obtained from 33 double-blind controlled clinical trials reported in the literature (1,092 patients). The incidence for group (2) was based on reports in clinical trials, in the literature, and on voluntary reports since marketing. The probability of a causal relationship exists between indomethacin and these adverse reactions, some of which have been reported only rarely. The adverse reactions reported with indomethacin capsules may occur with use of the suppositories. In addition, rectal irritation and tenesmus have been reported in patients who have received the capsules. Table 1: Summary of Adverse Reactions for Indomethacin Capsules Incidence greater than 1% Incidence less than 1% GASTROINTESTINAL nausea* with or without vomiting dyspepsia* (including indigestion, heartburn and epigastric pain) diarrhea abdominal distress or pain constipation anorexia bloating (includes distension) flatulence peptic ulcer gastroenteritis rectal bleeding proctitis single or multiple ulcerations, including perforation and hemorrhage of the esophagus, stomach, duodenum or small and large intestines intestinal ulceration associated with stenosis and obstruction gastrointestinal bleeding without obvious ulcer formation and perforation of preexisting sigmoid lesions (diverticulum, carcinoma, etc.) development of ulcerative colitis and regional ileitis ulcerative stomatitis toxic hepatitis and jaundice (some fatal cases have been reported) intestinal strictures (diaphragms) pancreatitis CENTRAL NERVOUS SYSTEM headache (11.7%) dizziness* vertigo somnolence depression and fatigue (including malaise and listlessness) anxiety (includes nervousness) muscle weakness involuntary muscle movements insomnia muzziness psychic disturbances including psychotic episodes mental confusion drowsiness light-headedness syncope paresthesia aggravation of epilepsy and parkinsonism depersonalization coma peripheral neuropathy convulsion dysarthria SPECIAL SENSES tinnitus ocular — corneal deposits and retinal disturbances, including those of the macula, have been reported in some patients on prolonged therapy with indomethacin capsules blurred vision diplopia hearing disturbances, deafness CARDIOVASCULAR None hypertension hypotension tachycardia chest pain congestive heart failure arrhythmia; palpitations METABOLIC None edema weight gain fluid retention flushing or sweating hyperglycemia glycosuria hyperkalemia INTEGUMENTARY none pruritus rash; urticaria petechiae or ecchymosis exfoliative dermatitis erythema nodosum loss of hair Stevens-Johnson syndrome erythema multiforme toxic epidermal necrolysis HEMATOLOGIC None leukopenia bone marrow depression anemia secondary to obvious or occult gastrointestinal bleeding aplastic anemia hemolytic anemia agranulocytosis thrombocytopenic purpura disseminated intravascular coagulation HYPERSENSITIVITY None acute anaphylaxis acute respiratory distress rapid fall in blood pressure resembling a shock-like state angioedema dyspnea asthma purpura angiitis pulmonary edema fever GENITOURINARY None hematuria vaginal bleeding proteinuria nephrotic syndrome interstitial nephritis BUN elevation renal insufficiency, including renal failure MISCELLANEOUS None epistaxis breast changes, including enlargement and tenderness, or gynecomastia *Reactions occurring in 3% to 9% of patients treated with indomethacin capsules. (Those reactions occurring in less than 3% of the patients are unmarked.) Causal relationship unknown: Other reactions have been reported but occurred under circumstances where a causal relationship could not be established. However, in these rarely reported events, the possibility cannot be excluded. Therefore, these observations are being listed to serve as alerting information to physicians: Cardiovascular: Thrombophlebitis Hematologic: Although there have been several reports of leukemia, the supporting information is weak Genitourinary: Urinary frequency A rare occurrence of fulminant necrotizing fasciitis, particularly in association with Group Aβ hemolytic streptococcus, has been described in persons treated with nonsteroidal anti-inflammatory agents, including indomethacin, sometimes with fatal outcome. 6.2 Postmarketing Experience Thefollowing adverse reactions have been identified during postapproval use of indomethacin. Because these reactions are reported voluntarily from apopulation of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Skinand Appendages: Exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and fixed drug eruption (FDE).

<table cellspacing="0" cellpadding="0" border="0" width="650"><col width="36%"/><col width="34.9230769230769%"/><col width="29.0769230769231%"/><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"><content styleCode="bold"><content styleCode="italics">Incidence greater than 1%</content></content><content styleCode="italics"/> </td><td colspan="2" styleCode="Rrule" valign="top"><content styleCode="bold"><content styleCode="italics">Incidence less than 1%</content></content><content styleCode="italics"/> </td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule" valign="top"><content styleCode="italics"> </content><content styleCode="italics">GASTROINTESTINAL</content><content styleCode="italics"/> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">nausea* with or without vomiting dyspepsia* (including indigestion, heartburn and epigastric pain) diarrhea abdominal distress or pain constipation </td><td styleCode="Rrule" valign="top">anorexia bloating (includes distension) flatulence peptic ulcer gastroenteritis rectal bleeding proctitis single or multiple ulcerations, including perforation and hemorrhage of the esophagus, stomach, duodenum or small and large intestines intestinal ulceration associated with stenosis and obstruction </td><td styleCode="Rrule" valign="top">gastrointestinal bleeding without obvious ulcer formation and perforation of preexisting sigmoid lesions (diverticulum, carcinoma, etc.) development of ulcerative colitis and regional ileitis ulcerative stomatitis toxic hepatitis and jaundice (some fatal cases have been reported) intestinal strictures (diaphragms) pancreatitis </td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule" valign="top"><content styleCode="italics">CENTRAL NERVOUS SYSTEM</content><content styleCode="italics"/> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">headache (11.7%) dizziness* vertigo somnolence depression and fatigue (including malaise and listlessness) </td><td styleCode="Rrule" valign="top">anxiety (includes nervousness) muscle weakness involuntary muscle movements insomnia muzziness psychic disturbances including psychotic episodes mental confusion drowsiness </td><td styleCode="Rrule" valign="top">light-headedness syncope paresthesia aggravation of epilepsy and parkinsonism depersonalization coma peripheral neuropathy convulsion dysarthria </td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule" valign="top"><content styleCode="italics">SPECIAL SENSES</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">tinnitus </td><td styleCode="Rrule" valign="top">ocular &#x2014; corneal deposits and retinal disturbances, including those of the macula, have been reported in some patients on prolonged therapy with indomethacin capsules </td><td styleCode="Rrule" valign="top">blurred vision diplopia hearing disturbances, deafness </td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule" valign="top"><content styleCode="italics">CARDIOVASCULAR</content><content styleCode="italics"/> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">None </td><td styleCode="Rrule" valign="top">hypertension hypotension tachycardia chest pain </td><td styleCode="Rrule" valign="top">congestive heart failure arrhythmia; palpitations </td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule" valign="top"><content styleCode="italics">METABOLIC</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">None </td><td styleCode="Rrule" valign="top">edema weight gain fluid retention flushing or sweating </td><td styleCode="Rrule" valign="top">hyperglycemia glycosuria hyperkalemia </td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule" valign="top"><content styleCode="italics">INTEGUMENTARY</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">none </td><td styleCode="Rrule" valign="top">pruritus rash; urticaria petechiae or ecchymosis </td><td styleCode="Rrule" valign="top">exfoliative dermatitis erythema nodosum loss of hair Stevens-Johnson syndrome erythema multiforme toxic epidermal necrolysis </td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule" valign="top"><content styleCode="italics">HEMATOLOGIC</content><content styleCode="italics"/> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">None </td><td styleCode="Rrule" valign="top">leukopenia bone marrow depression anemia secondary to obvious or occult gastrointestinal bleeding </td><td styleCode="Rrule" valign="top">aplastic anemia hemolytic anemia agranulocytosis thrombocytopenic purpura disseminated intravascular coagulation </td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule" valign="top"><content styleCode="italics">HYPERSENSITIVITY</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">None </td><td styleCode="Rrule" valign="top">acute anaphylaxis acute respiratory distress rapid fall in blood pressure resembling a shock-like state angioedema </td><td styleCode="Rrule" valign="top">dyspnea asthma purpura angiitis pulmonary edema fever </td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule" valign="top"><content styleCode="italics">GENITOURINARY</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">None </td><td styleCode="Rrule" valign="top">hematuria vaginal bleeding proteinuria nephrotic syndrome interstitial nephritis </td><td styleCode="Rrule" valign="top">BUN elevation renal insufficiency, including renal failure </td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule" valign="top"><content styleCode="italics">MISCELLANEOUS </content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top">None </td><td styleCode="Rrule" valign="top">epistaxis breast changes, including enlargement and tenderness, or gynecomastia </td><td styleCode="Rrule" valign="top"> </td></tr><tr><td colspan="3" styleCode="Lrule Rrule" valign="top">*Reactions occurring in 3% to 9% of patients treated with indomethacin capsules. (Those reactions occurring in less than 3% of the patients are unmarked.) </td></tr></tbody></table>