• Indicated for treatment of mild to moderate acute pain in adults.

TIVORBEX is not indicated for long-term treatment.

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.

TIVORBEX is contraindicated in the setting of coronary artery bypass graft (CABG) surgery and in patients with aspirin-sensitive asthma.

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.

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

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.

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 TIVORBEX 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

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.

NSAIDs, including TIVORBEX, 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.

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

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.

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.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as TIVORBEX. Some of these events have been fatal or life-threatening.

Anemia has occurred in NSAID-treated patients. NSAIDs, including TIVORBEX, may increase the risk of bleeding events. Comorbid 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.

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

TIVORBEX 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 TIVORBEX.

Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment.

Corneal deposits and retinal disturbances, including those of the macula, have been observed in some patients who had received prolonged therapy with TIVORBEX.

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, TIVORBEX is contraindicated in patients with this form of aspirin sensitivity.

Indomethacin and triamterene should not be administered together.

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.

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.

The concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.

Indomethacin and anticoagulants such as warfarin have a 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.

Concomitant use of TIVORBEX and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding.

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.

NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance.

Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).

Concomitant use of TIVORBEX and cyclosporine may increase cyclosporine nephrotoxicity.

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. Combined use with diflunisal may be particularly hazardous because diflunisal causes significantly higher plasma levels of indomethacin. In some patients, combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage.The concomitant use of indomethacin with other NSAIDs or salicylates , especially diflunisal, is not recommended.

Concomitant use of TIVORBEX and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information).

When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased.

False-negative results in the dexamethasone suppression test (DST) in patients being treated with indomethacin have been reported.

NSAIDs are associated with reversible infertility. Consider withdrawal of TIVORBEX in women who have difficulties conceiving.

Use of NSAIDs, including TIVORBEX, 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.

Avoid use of NSAIDs, including TIVORBEX, in pregnant women at about 30 weeks gestation and later. NSAIDs, including TIVORBEX, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age.

Data from observational studies regarding potential embryo-fetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. Anima studies: toxicity and death.

Based on available published clinical data, indomethacin may be present in human milk.

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• Use in patients under the age of 18. GoToSource 

• Prophylaxis in preterm infants. GoToSource 

• Cognitive decline in alzheimer’s disease. GoToSource 

• Uremic pericarditis. GoToSource 

• Langerhans cell histiocytosis. GoToSource 

• Decrease intracranial cerebral pressure and improve cerebral pressure perfusion in severe traumatic brain injury. GoToSource

Heart attacks and strokes. GoToSource

Gastrointestinal bleeding, hypertension (high blood pressure), kidney failure and birth defects. GoToSource

Congestive heart failure. GoToSource

Hyperkalemia (elevated blood potassium level). GoToSource

Anaphylaxis (life-threatening allergic reaction). GoToSource

Toxic epidermal necrolysis (life-threatening skin condition). GoToSource

Aplastic anemia. GoToSource

Liver injury. GoToSource

Psychiatric side effects including anxiety, fear, agitation, affective lability, depersonalization, paranoia and hallucinations. GoToSource

Retinopathy (disease of the retina). GoToSource

Cystitis (inflammation of the bladder). GoToSource

Lawsuits filed for kidney failure.