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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].
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 Gastrointestinal (GI) Effects].
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 evaluation 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.
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 evaluated 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.
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].
Congestive Heart Failure And Edema
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.
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].
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 hyporeninemichypoaldosteronism state.
Advanced Renal Disease
No information is available from controlled clinical studies regarding the use of indomethacin in patients with advanced renal disease. Therefore, treatment with TIVORBEX is not recommended in patients with advanced renal disease. If TIVORBEX therapy must be initiated, monitor patient renal function closely.
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].
Seek emergency help in cases where an anaphylactic reaction occurs.
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.
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].
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].
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.
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.
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.
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].
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.
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.
Patient Counseling Information
See FDA-approved patient labeling (Medication Guide). Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.
NSAIDs, including TIVORBEX, may cause serious CV side effects, such as myocardial infarction or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, advise patients to be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and to ask for medical advice when observing any indicative sign or symptoms. Inform patients of the importance of this follow-up [see WARNINGS AND PRECAUTIONS].
NSAIDs, including TIVORBEX, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, advise patients to be alert for the signs and symptoms of ulcerations and bleeding, and to ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Inform patients of the importance of this follow-up [see WARNINGS AND PRECAUTIONS].
Adverse Skin Reactions
NSAIDs, like TIVORBEX, can cause serious skin side effects such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which may result in hospitalizations and even death. Although serious skin reactions may occur without warning, advise patients to be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and to ask for medical advice when observing any indicative signs or symptoms. Advise patients to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible [see WARNINGS AND PRECAUTIONS].
Weight Gain And Edema
Advise patients to promptly report to their physicians signs or symptoms of unexplained weight gain or edema during treatment with TIVORBEX [see WARNINGS AND PRECAUTIONS].
Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop therapy and seek immediate medical therapy [see WARNINGS AND PRECAUTIONS].
Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see WARNINGS AND PRECAUTIONS].
Inform pregnant women to avoid use of TIVORBEX and other NSAIDs starting at 30 weeks gestation, [see WARNINGS AND PRECAUTIONS and Use In Specific Populations].
Carcinogenesis, Mutagenesis, and Impairment Of Fertility
In an 81-week chronic oral toxicity study in the rat at doses up to 1 mg/kg/day (0.08 times the MRHD on a mg/m² basis), indomethacin had no tumorigenic effect. Indomethacin produced no neoplastic or hyperplastic changes related to treatment in carcinogenic studies in the rat (dosing period 73 to 110 weeks) and the mouse (dosing period 62 to 88 weeks) at doses up to 1.5 mg/kg/day (0.06 times [mice] and 0.12 times [rats] the MRHD on a mg/m² basis, respectively).
Indomethacin did not have any mutagenic effect in in vitro bacterial tests and a series of in vivo tests including the host-mediated assay, sex-linked recessive lethals in Drosophila, and the micronucleus test in mice.
Impairment of Fertility
Indomethacin at dosage levels up to 0.5 mg/kg/day had no effect on fertility in mice in a two generation reproduction study (0.02 times the MRHD on a mg/m² basis) or a two litter reproduction study in rats (0.04 times the MRHD on a mg/m² basis).
Use In Specific Populations
Pregnancy Category C prior to 30 weeks gestation;
Category D starting at 30 weeks gestation.
There are no adequate and well-controlled studies of TIVORBEX in pregnant women. 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. TIVORBEX can cause fetal harm when administered starting at 30 weeks gestation. If the drug is used during this time period in pregnancy, the patient should be apprised of the potential hazard to the fetus. Prior to 30 weeks gestation, TIVORBEX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In animal reproduction studies, retarded fetal ossification was observed with administration of indomethacin to mice and rats during organogenesis at doses 0.16 and 0.32 times, respectively, the maximum recommended human dose (MRHD, 120 mg).
Fetal and Neonatal Adverse Reactions
The known effects of indomethacin and other NSAIDs on the human fetus during the third trimester of pregnancy include: constriction of the ductus arteriosus, tricuspid incompetence, and pulmonary hypertension; non-closure of the ductus arteriosus postnatally which may be resistant to medical management; myocardial degenerative changes, platelet dysfunction with resultant bleeding, intracranial bleeding, renal dysfunction or failure, renal injury/dysgenesis which may result in prolonged or permanent renal failure, oligohydramnios, gastrointestinal bleeding or perforation, and increased risk of necrotizing enterocolitis.
Labor or Delivery
The effects of TIVORBEX on labor and delivery in pregnant women are unknown. In rat studies, maternal exposure to NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, increased the incidence of dystocia, delayed parturition, and decreased pup survival.
Reproductive studies were conducted in mice and rats at dosages of 0.5, 1.0, 2.0, and 4.0 mg/kg/day. Except for retarded fetal ossification at 4 mg/kg/day (0.16 times [mice] and 0.32 times [rats] the MRHD on a mg/m² basis, respectively) considered secondary to the decreased average fetal weights, no increase in fetal malformations was observed as compared with control groups. Other studies in mice reported in the literature using higher doses (5 to 15 mg/kg/day, 0.20 to 0.60 times MRHD on a mg/m² basis) have described maternal toxicity and death, increased fetal resorptions, and fetal malformations. Comparable studies in rodents using high doses of aspirin have shown similar maternal and fetal effects.
Maternal indomethacin administration of 4.0 mg/kg/day during the last 3 days of gestation was associated with an increased incidence of neuronal necrosis in the diencephalon in the live-born fetuses however no increase in neuronal necrosis was observed at 2.0 mg/kg/day as compared to the control groups. Administration of 0.5 or 4.0 mg/kg/day to offspring during the first 3 days of life did not cause an increase in neuronal necrosis at either dose level.
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.
The safety and effectiveness of TIVORBEX in pediatric patients 17 years of age and younger has not been established.
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].
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].This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 3/5/2014
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