Indocin Suspension

Cardiovascular Thrombotic Events 

• Increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. 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. Higher doses showed increased risk for CV thrombotic events. 

• Use the lowest effective dose for the shortest duration possible to minimize the potential risk for an adverse CV event in NSAID-treated patients. Inform patients 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.

• Status Post Coronary Artery Bypass Graft (CABG) Surgery: 

• NSAIDs are contraindicated in the setting of CABG.

• Post-MI Patients: 

• Avoid the use of indomethacin in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. 

• Monitor for signs of cardiac ischemia if indomethacin is used in patients with a recent MI.

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. 

• 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. 

• Fatal GI events occurred mostly 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. 

• Promptly initiate evaluation and treatment if a serious GI adverse event is suspected, and discontinue indomethacin until a serious GI adverse event is ruled out. 

• Monitor closely for evidence of GI bleeding in the setting of concomitant use of low-dose aspirin for cardiac prophylaxis.

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. 

• Inform about the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). 

• Discontinue indomethacin immediately and perform a clinical evaluation if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (eg, eosinophilia, rash, etc.).

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. Concomitant use with angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may impair response to these therapies when taking NSAIDs. 

• Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy.

Heart Failure and Edema

• Fluid retention and edema have been observed in some patients treated with NSAIDs. 

• Indomethacin may blunt the CV effects of several therapeutic agents used to treat these medical conditions (eg, diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]).

• Avoid use in severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. Monitor for signs of worsening heart failure if indomethacin is used in patients with severe heart failure.

Renal Toxicity and Hyperkalemia

• Renal Toxicity:

• Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. 

• Greatest risk seen in patients 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. 

• Prior to initiating, correct volume status in dehydrated or hypovolemic patients. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of indomethacin. 

• Avoid the use of indomethacin in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. 

• Monitor for signs of worsening renal function if indomethacin is used in patients with advanced renal disease.

• Indomethacin and triamterene should not be administered together due to the risk of reversible acute renal failure.

• 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.

• Consider the potential effects of indomethacin and potassium-sparing diuretics on potassium levels and renal function when these agents are administered concurrently.

Anaphylactic Reactions 

• Seek emergency help if an anaphylactic reaction occurs. 

Exacerbation of Asthma Related to Aspirin Sensitivity

• 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.

• Indomethacin is contraindicated in patients with this form of aspirin sensitivity due to the cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients. 

• Monitor for changes in the signs and symptoms of asthma when indomethacin is used in patients with preexisting asthma (without known aspirin sensitivity).  

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. 

• 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.

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. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. 

• Discontinue and evaluate the patient immediately if such signs or symptoms are present.

Fetal Toxicity

• Premature Closure of Fetal Ductus Arteriosus: 

• Avoid use of NSAIDS, including indomethacin, in pregnant women at about 30 weeks of 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.

• 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.

Hematologic Toxicity

• Monitor hemoglobin or hematocrit if signs or symptoms of anemia develop.

• May increase risk of bleeding events with comorbid conditions such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet agents (eg, aspirin), serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs). Monitor for signs of bleeding.

Masking of Inflammation and Fever

• May diminish the utility of diagnostic signs in detecting infections. 

Laboratory Monitoring

• Consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically due to serious GI bleeding, hepatotoxicity, and renal injury which may occur without warning symptoms or signs. 

Central Nervous System Effects

• May aggravate depression or other psychiatric disturbances, epilepsy, and parkinsonism, and should be used with considerable caution in patients with these conditions. 

• Discontinue indomethacin if severe CNS adverse reactions develop.

• May cause drowsiness; therefore, caution patients about engaging in activities requiring mental alertness and motor coordination, such as driving a car. May also cause headaches. Headache which persists despite dosage reduction requires cessation of therapy with indomethacin.

Ocular Effects

• Corneal deposits and retinal disturbances, including those of the macula, may occur with prolonged indomethacin therapy. 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, perform ophthalmologic examination at periodic intervals in patients receiving prolonged therapy. Indomethacin is not indicated for long-term treatment.