2.1 Initial Dosing

For treatment of mild to moderate acute pain, the dosage is 20 mg three times daily or 40 mg two or three times daily. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals.

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, myocardial infarction (MI), and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a 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, use the lowest effective dose 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. Inform patients about the signs and/or symptoms of serious CV events and the steps to take if they occur.

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 MI and stroke [see Contraindications (4)].

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, does increase the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2)].

5.2 Gastrointestinal (GI) Effects – Risk of GI Ulceration, Bleeding, and Perforation

NSAIDs, including TIVORBEX, 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 a 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 3-6 months, and in about 2%-4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term NSAID therapy is not without risk.

In patients taking indomethacin, intestinal ulceration has been associated with stenosis and obstruction. Gastrointestinal bleeding without obvious ulcer formation and perforation of pre-existing 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.

Prescribe NSAIDs, including TIVORBEX, with extreme caution in patients with a prior history of ulcer disease or GI bleeding. Patients with a prior history of peptic ulcer disease and/or GI bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a 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 longer duration of NSAID therapy, concomitant use of oral corticosteroids or anticoagulants, 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, use the lowest effective dose 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 eva luation and treatment if a serious GI adverse event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternative therapies that do not include NSAIDs should be considered.

5.3 Hepatic Effects

Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs, including TIVORBEX. 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 abnormal liver test values have occurred, should be eva luated for evidence of the development of a 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.), discontinue TIVORBEX immediately.

5.4 Hypertension

NSAIDs, including TIVORBEX, can lead to new onset or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events.

Use NSAIDs, including TIVORBEX, with caution in patients with hypertension. Monitor blood pressure (BP) closely during the initiation of NSAID treatment and throughout the course of therapy.

Patients taking ACE inhibitors, thiazides or loop diuretics or beta-adrenoceptor blocking agents may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7.1, 7.3, 7.7)].

5.5 Congestive Heart Failure and Edema

Fluid retention and edema have been observed in some patients taking NSAIDs. Use TIVORBEX with caution in patients with fluid retention or heart failure.

In a 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.

5.6 Renal Effects

Use caution when initiating treatment with TIVORBEX in patients with considerable dehydration.

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 a nonsteroidal anti-inflammatory drug may cause a 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 [see Drug Interactions (7.1, 7.7)].

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 a hyporeninemic-hypoaldosteronism state.

5.7 Anaphylactic Reactions

As with other NSAIDs, anaphylactic reactions may occur in patients without known prior exposure to TIVORBEX. TIVORBEX is contraindicated in 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 (4)].

Seek emergency help in cases where an anaphylactic reaction occurs.

5.8 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.

5.9 Skin Reactions

NSAIDs, including TIVORBEX, 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. Patients should be informed about the signs and symptoms of serious skin manifestations, and discontinue the use of TIVORBEX at the first appearance of skin rash or any other sign of hypersensitivity [see Contraindications (4)].

5.10 Fetal Toxicity

Starting at 30 weeks gestation, TIVORBEX and other NSAIDs should be avoided by pregnant women as premature closure of the ductus arteriosus in the fetus may occur. If this drug is used during this time period in pregnancy, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)].

5.11 Corticosteroid Treatment

TIVORBEX cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to exacerbation of corticosteroid-responsive illness. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids.

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 infectious complications of presumed noninfectious, painful conditions.

5.13 Hematological Effects

Anemia may occur in patients receiving NSAIDs, including TIVORBEX. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. In patients receiving long-term therapy with NSAIDs, including TIVORBEX, check hemoglobin or hematocrit if they exhibit any signs or symptoms of anemia or blood loss. TIVORBEX is not indicated for long-term treatment.

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. Carefully monitor patients treated with TIVORBEX who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants.

5.14 Use in Patients with 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 NSAIDs has been reported in such aspirin-sensitive patients, TIVORBEX is contraindicated in patients with this form of aspirin sensitivity and should be used with caution in all patients with preexisting asthma [see Contraindications (4)].

5.15 Monitoring

Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. For patients on long-term treatment with NSAIDs, periodically check their CBC and chemistry profile including liver function tests. Discontinue TIVORBEX 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. TIVORBEX is not indicated for long-term treatment.

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 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.

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.

Five hundred and fifty-four patients (554) received TIVORBEX 20 mg or 40 mg for up to 48 hours in two double-blind, placebo-controlled, clinical trials of acute pain following bunionectomy. The most frequent adverse reactions in these trials are summarized below.

The following adverse reactions have been identified during post approval use of indomethacin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Gastrointestinal: 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 pre-existing 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).

Cardiovascular: hypertension, hypotension, tachycardia, chest pain, congestive heart failure, arrhythmia, palpitations.

Hematologic: leukopenia, bone marrow depression, anemia secondary to obvious or occult gastrointestinal bleeding, aplastic anemia, hemolytic anemia, agranulocytosis, thrombocytopenic purpura, disseminated intravascular coagulation.

Central Nervous System: anxiety (includes nervousness), muscle weakness, involuntary muscle movements, insomnia, confusion, psychic disturbances including psychotic episodes, mental confusion, drowsiness, light-headedness, syncope, paresthesia, aggravation of epilepsy and parkinsonism, depersonalization, coma, peripheral neuropathy, convulsion, dysarthria.

Hypersensitivity: acute anaphylaxis, acute respiratory distress rapid fall in blood pressure resembling a shock-like state, angioedema, dyspnea, asthma, purpura, angiitis, pulmonary edema, fever.

Metabolic: edema, weight gain, fluid retention, flushing or sweating, hyperglycemia, glycosuria, hyperkalemia

Genitourinary: hematuria, vaginal bleeding, proteinuria, nephrotic syndrome, interstitial nephritis: BUN elevation, renal insufficiency, including renal failure.

Special Senses: ocular — corneal deposits and retinal disturbances, including those of the macula, have been reported in some patients on prolonged therapy with indomethacin; blurred vision, diplopia, hearing disturbances, deafness.

Skin and Appendages: pruritus, rash, urticaria, petechiae or ecchymosis, exfoliative dermatitis, erythema nodosum, loss of hair, Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis.

Miscellaneous: epistaxis, breast changes, including enlargement and tenderness, gynecomastia

7.1 ACE-inhibitors and Angiotensin II Antagonists

NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (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 co-administration 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 [see Warnings and Precautions (5.6)].

7.2 Aspirin

When administered with aspirin, indomethacin's protein binding is reduced, although the clearance of free indomethacin is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of indomethacin and aspirin is not generally recommended because of the potential of increased adverse effects.

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 a clinical study of the combined use of indomethacin and aspirin, the incidence of gastrointestinal side effects was significantly increased with combined therapy.

In a study in normal volunteers, it was found that chronic concurrent administration of 3.6 g of aspirin per day decreases indomethacin blood levels approximately 20%.

7.3 Beta-adrenoceptor Blocking Agents

Blunting of the antihypertensive effect of beta-adrenoceptor blocking agents by NSAIDs 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.

7.4 Cyclosporine

Administration of NSAIDs concomitantly with cyclosporine has been associated with an increase in cyclosporine-induced toxicity, possibly due to decreased synthesis of renal prostacyclin. Use caution when NSAIDs are administered concomitantly with cyclosporine. Carefully monitor patients with impaired renal function.

7.5 Diflunisal

In 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.

7.6 Digoxin

Indomethacin 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.

7.7 Diuretics

Clinical studies, as well as post-marketing observations, have shown that NSAIDs can reduce the natriuretic effect of furosemide and thiazides in some patients. 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 eva luating plasma renin activity in hypertensive patients.

It has been reported that the addition of 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.

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, observe patients closely for signs of renal failure, as well as to assure diuretic efficacy [see Warnings and Precautions (5.6)].

7.8 Lithium

NSAIDs, including indomethacin, have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, observe patients carefully for signs of lithium toxicity. See the Prescribing Information 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.

7.9 Methotrexate

NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Use caution when NSAIDs are administered concomitantly with methotrexate.

7.10 NSAIDs

The 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.

7.11 Anticoagulants

Caution should be exercised when NSAIDs, such as indomethacin, and anticoagulants are administered concomitantly. The effects of anticoagulants (such as warfarin) and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than that with use of either drug alone.

7.12 Probenecid

When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased. Therefore, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect. When increases in the dose of indomethacin are made, they should be made carefully and in small increments.

8.1 Pregnancy

8.3 Nursing Mothers

Based on available published data, indomethacin may be present in human milk. 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 µg/day or 4.5 µg/ 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. The developmental and health benefits of human milk feeding should be considered along with the mother's clinical need for TIVORBEX and any potential adverse effects on the human milk-fed child from the drug or from the underlying maternal condition. Exercise caution when TIVORBEX is administered to a nursing woman.

8.4 Pediatric Use

The safety and effectiveness of TIVORBEX in pediatric patients 17 years of age and younger has not been established.

8.5 Geriatric Use

As with any NSAIDs, caution should be exercised in treating the elderly (65 years and older) since advancing age appears to increase the possibility of adverse reactions. 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 and Precautions (5.2)].

Indomethacin may cause confusion or rarely, psychosis [see Adverse Reactions (6.2)]; 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 and Precautions (5.6)].

12.1 Mechanism of Action

TIVORBEX is a NSAID with analgesic and antipyretic and analgesic properties.

The mechanism of action of TIVORBEX, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2).

Indomethacin is a potent inhibitor of prostaglandin synthesis in vitro. Indomethacin concentrations are reached during therapy which have been demonstrated to produce in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Since indomethacin is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues.

12.3 Pharmacokinetics

The relative bioavailability of TIVORBEX 40 mg capsules was compared to indomethacin immediate-release (IR) capsules 50 mg in 38 healthy subjects under fasted conditions in a single-dose crossover study.

TIVORBEX (indomethacin) 40 mg capsules do not result in an equivalent systemic exposure to 50 mg indomethacin IR capsules.

When taken under fasted conditions, a 20% lower dose of indomethacin in TIVORBEX 40 mg capsules resulted in a 21% lower mean systemic exposure (AUCinf) and an equivalent mean peak concentration (Cmax) compared to 50 mg indomethacin IR capsules. The median time to reach peak concentrations (Tmax) was 1.67 hours and 2.02 hours for TIVORBEX capsules and Indomethacin IR capsules, respectively.

13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility

Storage

Store at 25ºC (77ºF); excursions permitted to 15ºC-30ºC (59ºF-86ºF). [see USP Controlled Room Temperature].

Store in the original container and keep the bottle tightly closed to protect from moisture and light. Dispense in a tight container if package is subdivided.