WARNING AND CAUTIONS

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 TIVORBEX in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure (5.5) Renal T oxicity: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia.

Avoid use of TIVORBEX in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function (5.6) Anaphylactic R eactions: Seek emergency help if an anaphylactic reaction occurs (5.7) Exacerbation of Asthma Related to Aspirin Sensitivity: TIVORBEX is contraindicated in patients with aspirin-sensitive asthma.

Monitor patients with preexisting asthma (without aspirin sensitivity) (5.8) Serious S kin R eactions: Discontinue TIVORBEX at first appearance of skin rash or other signs of hypersensitivity (5.9) Premature C losure of F etal D uctus A rteriosus: 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 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 P ost C oronary A rtery B ypass G raft (CABG) S urgery Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke.

NSAIDs are contraindicated in the setting of CABG [see Contraindications ( 4 )].

Post-MI P atients 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 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.

5.2 G astrointestinal 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 3-6 months, and in about 2%-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 G I 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 [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 TIVORBEX immediately, and perform a clinical evaluation of the patient.

5.4 Hypertension 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 [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 TIVORBEX in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure.

If TIVORBEX is 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 TIVORBEX in patients with advanced renal disease.

The renal effects of TIVORBEX may hasten the progression of renal dysfunction in patients with preexisting renal disease.

Correct volume status in dehydrated or hypovolemic patients prior to initiating TIVORBEX.

Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of TIVORBEX [see Drug Interactions ( 7 )].

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

If TIVORBEX 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 Anaphylact ic 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, TIVORBEX is contraindicated in patients with this form of aspirin sensitivity [see Contraindications ( 4 )].

When TIVORBEX is 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 TIVORBEX at the first appearance of skin rash or any other sign of hypersensitivity.

TIVORBEX 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 TIVORBEX, 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 a patient treated with TIVORBEX has any signs or symptoms of anemia, monitor hemoglobin or hematocrit.

NSAIDs, including TIVORBEX, 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 TIVORBEX 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 a CBC and a chemistry profile periodically [see Warnings and Precautions ( 5.2 , 5.3 , 5.6 )].

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

Discontinue TIVORBEX if severe CNS adverse reactions develop.

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.

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 TIVORBEX.

Be alert to the possible association between the changes noted and TIVORBEX.

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.

TIVORBEX is not indicated for long-term treatment.