ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. Adverse reaction information was derived from blinded-controlled and open-labeled clinical trials and from worldwide marketing experience. In the description below, rates of the more common events (greater than 1%) and many of the less common events (less than 1%) represent results of U.S. clinical studies.Of the 1,677 patients who received nabumetone during U.S. clinical trials, 1,524 were treated for at least month, 1,327 for at least months, 929 for at least year, and 750 for at least years. More than 300 patients have been treated for years or longer.The most frequently reported adverse reactions were related to the gastrointestinal tract and included diarrhea, dyspepsia, and abdominal pain.. Incidence >= 1% Probably Causally Related. GastrointestinalDiarrhea (14%), dyspepsia (13%), abdominal pain (12%), constipation2, flatulence2, nausea2, positive stool guaiac2, dry mouth, gastritis, stomatitis, vomiting.Central Nervous SystemDizziness2, headache2, fatigue, increased sweating, insomnia, nervousness, somnolence.DermatologicPruritus2, rash2.Special SensesTinnitus2.MiscellaneousEdema2.2 Incidence of reported reaction between 3% and 9%. Reactions occurring in 1% to 3% of the patients are unmarked.. Incidence 1% Probably Causally Related+3 GastrointestinalAnorexia, jaundice, duodenal ulcer, dysphagia, gastric ulcer, gastroenteritis, gastrointestinal bleeding, increased appetite, liver function abnormalities, melena, hepatic failure.Central Nervous SystemAsthenia, agitation, anxiety, confusion, depression, malaise, paresthesia, tremor, vertigo.DermatologicBullous eruptions, photosensitivity, urticaria, pseudoporphyria cutanea tarda, toxic epidermal necrolysis, erythema multiforme, Stevens-Johnson syndrome. CardiovascularVasculitis.MetabolicWeight Gain.RespiratoryDyspnea, eosinophilic pneumonia, hypersensitivity pneumonitis, idiopathic interstitial pneumonitis. GenitourinaryAlbuminuria, azotemia, hyperuricemia, interstitial nephritis, nephrotic syndrome, vaginal bleeding, renal failure.Special SensesAbnormal vision.Hematologic/LymphaticThrombocytopenia.HypersensitivityAnaphylactoid reaction, anaphylaxis, angioneurotic edema.3+ Adverse reactions reported only in worldwide postmarketing experience or in the literature, not seen in clinical trials, are considered rarer and are italicized.. Incidence 1% Causal Relationship Unknown. GastrointestinalBilirubinuria, duodenitis, eructation, gallstones, gingivitis, glossitis, pancreatitis, rectal bleeding.Central Nervous SystemNightmares.DermatologicAcne, alopecia.CardiovascularAngina, arrhythmia, hypertension, myocardial infarction, palpitations, syncope, thrombophlebitis.RespiratoryAsthma, cough.GenitourinaryDysuria, hematuria, impotence, renal stones.Special SensesTaste disorder.Body as WholeFever, chills.Hematologic/LymphaticAnemia, leukopenia, granulocytopenia.Metabolic/NutritionalHyperglycemia, hypokalemia, weight loss.

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. Nabumetone is non-steroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic properties in pharmacologic studies. As with other non-steroidal anti-inflammatory agents, its mode of action is not known; however, the ability to inhibit prostaglandin synthesis may be involved in the anti-inflammatory effect.The parent compound is prodrug, which undergoes hepatic biotransformation to the active component, 6-methoxy-2-naphthylacetic acid (6MNA), that is potent inhibitor of prostaglandin synthesis.6-methoxy-2-naphthylacetic acid (6MNA)It is acidic and has an n-octanol: phosphate buffer partition coefficient of 0.5 at pH 7.4.. 6MNA. Pharmacokinetics. After oral administration, approximately 80% of radiolabeled dose of nabumetone is found in the urine, indicating that Nabumetone is well absorbed from the gastrointestinal tract. Nabumetone itself is not detected in the plasma because, after absorption, it undergoes rapid biotransformation to the principal active metabolite, 6-methoxy-2-naphthylacetic acid (6MNA). Approximately 35% of 1,000 mg oral dose of nabumetone is converted to 6MNA and 50% is converted into unidentified metabolites which are subsequently excreted in the urine. Following oral administration of nabumetone, 6MNA exhibits pharmacokinetic characteristics that generally follow one-compartment model with first order input and first order elimination.6MNA is more than 99% bound to plasma proteins. The free fraction is dependent on total concentration of 6MNA and is proportional to dose over the range of 1,000 mg to 2,000 mg. It is 0.2% to 0.3% at concentrations typically achieved following administration of 1,000 mg of nabumetone and is approximately 0.6% to 0.8% of the total concentrations at steady state following daily administration of 2,000 mg.Steady-state plasma concentrations of 6MNA are slightly lower than predicted from single-dose data. This may result from the higher fraction of unbound 6MNA which undergoes greater hepatic clearance.Coadministration of food increases the rate of absorption and subsequent appearance of 6MNA in the plasma but does not affect the extent of conversion of nabumetone into 6MNA. Peak plasma concentrations of 6MNA are increased by approximately one third.Coadministration with an aluminum-containing antacid had no significant effect on the bioavailability of 6MNA.Table 1: Mean Pharmacokinetic Parameters of Nabumetone Active Metabolite (6MNA) at Steady State Following Oral Administration of 1,000 mg or 2,000 mg Doses of NabumetoneAbbreviation(units)Young AdultsMean +- SD1,000 mgn 31Young AdultsMean +- SD2,000 mgn 12ElderlyMean +- SD1,000 mgn 27 Tmax (hr) 3.0 (1.0 to 12.0) 2.5 (1.0 to 8.0) 4.0 (1.0 to 10.0) 1/2 (hr) 22.5 +- 3.7 26.2 +- 3.7 29.8 +- 8.1 CLss/F (mL/min) 26.1 +- 17.3 21.0 +- 4.0 18.6 +- 13.4 Vdss/F (L) 55.4 +- 26.4 53.4 +- 11.3 50.2 +- 25.3The simulated curves in the graph below illustrate the range of active metabolite plasma concentrations that would be expected from 95% of patients following 1,000 mg to 2,000 mg doses to steady state. The cross-hatched area represents the expected overlap in plasma concentrations due to intersubject variation following oral administration of 1,000 mg to 2,000 mg of nabumetone.Nabumetone Active Metabolite (6MNA) Plasma Concentrations at Steady State Following Once-Daily Dosing of Nabumetone 1,000 mg (n 31) 2,000 mg (n 12)6MNA undergoes biotransformation in the liver, producing inactive metabolites that are eliminated as both free metabolites and conjugates. None of the known metabolites of 6MNA has been detected in plasma. Preliminary in vivo and in vitro studies suggest that unlike other NSAIDs, there is no evidence of enterohepatic recirculation of the active metabolite. Approximately 75% of radiolabeled dose was recovered in urine in 48 hours. Approximately 80% was recovered in 168 hours. further 9% appeared in the feces. In the first 48 hours, metabolites consisted of: -nabumetone, unchanged not detectable -6-methoxy-2-naphthylacetic acid(6MNA), unchanged <1% -6MNA, conjugated 11% -6-hydroxy-2-naphthylacetic acid(6HNA), unchanged 5% -6HNA, conjugated 7% -4-(6-hydroxy-2-naphthyl)-butan-2-ol, Conjugated 9% -O-desmethyl-nabumetone, conjugated 7% -unidentified minor metabolites34% Total Dose: 73% Following oral administration of dosages of 1,000 mg to 2,000 mg to steady state, the mean plasma clearance of 6MNA is 20 to 30 mL/min and the elimination half-life is approximately 24 hours.. Figure. Elderly Patients. Steady-state plasma concentrations in elderly patients were generally higher than in young healthy subjects (see Table for summary of pharmacokinetic parameters).. Renal Insufficiency. In moderate renal insufficiency patients (creatinine clearance 30 to 49 mL/min), the terminal half-life of 6MNA was increased by approximately 50% (39.2 +- 7.8 hrs, = 12) compared to the normal subjects (26.9 +- 3.3 hrs, = 13), and there was 50% increase in the plasma levels of unbound 6MNA.Additionally, the renal excretion of 6MNA in the moderate renal impaired patients decreased on average by 33% compared to that in the normal patients. similar increase in the mean terminal half-life of 6MNA was seen in small study of patients with severe renal dysfunction (creatinine clearance 30 mL/min). In patients undergoing hemodialysis, steady-state plasma concentrations of the active metabolite 6MNA were similar to those observed in healthy subjects. Due to extensive protein binding, 6MNA is not dialyzable.Dosage adjustment of nabumetone generally is not necessary in patients with mild renal insufficiency (>= 50 mL/min). Caution should be used in prescribing nabumetone to patients with moderate or severe renal insufficiency. The maximum starting doses of nabumetone in patients with moderate or severe renal insufficiency should not exceed 750 mg or 500 mg, respectively once daily. Following careful monitoring of renal function in patients with moderate or severe renal insufficiency, daily doses may be increased to maximum of 1,500 mg and 1,000 mg, respectively (see WARNINGS, Renal Effects).. Hepatic Impairment. Data in patients with severe hepatic impairment are limited. Biotransformation of nabumetone to 6MNA and the further metabolism of 6MNA to inactive metabolites is dependent on hepatic function and could be reduced in patients with severe hepatic impairment (history of or biopsy-proven cirrhosis).. Special Studies. Gastrointestinal. Nabumetone was compared to aspirin in inducing gastrointestinal blood loss. Food intake was not monitored. Studies utilizing 51Cr-tagged red blood cells in healthy males showed no difference in fecal blood loss after or weeks administration of 1,000 mg or 2,000 mg of nabumetone daily when compared to either placebo-treated or non-treated subjects. In contrast, aspirin 3,600 mg daily produced an increase in fecal blood loss when compared to subjects who received nabumetone, placebo, or no treatment. The clinical relevance of the data is unknown.The following endoscopy trials entered patients who had been previously treated with NSAIDs. These patients had varying baseline scores and different courses of treatment. The trials were not designed to correlate symptoms and endoscopy scores. The clinical relevance of these endoscopy trials, i.e., either G.I. symptoms or serious G.I. events, is not known.Ten endoscopy studies were conducted in 488 patients who had baseline and post-treatment endoscopy. In clinical trials that compared total of 194 patients on 1,000 mg of nabumetone daily or naproxen 250 mg or 500 mg twice daily for to 12 weeks, treatment with nabumetone resulted in fewer patients with endoscopically detected lesions (> mm). In trials total of 101 patients administered 1,000 mg or 2,000 mg of nabumetone daily or piroxicam 10 mg to 20 mg for to 10 days, there were fewer patients treated with nabumetone with endoscopically detected lesions. In trials of total of 47 patients on 1,000 mg of nabumetone daily or indomethacin 100 mg to 150 mg daily for to weeks, the endoscopy scores were higher with indomethacin. Another 12 week trial in total of 171 patients compared the results of treatment with 1,000 mg of nabumetone daily to ibuprofen 2,400 mg/day and ibuprofen 2,400 mg/day plus misoprostol 800 mcg/day. The results showed that patients treated with nabumetone had lower number of endoscopically detected lesions (> mm) than patients treated with ibuprofen alone but comparable to the combination of ibuprofen plus misoprostol. The results did not correlate with abdominal pain.. Other. In week, repeat-dose studies in healthy volunteers, 1,000 mg of nabumetone daily had little effect on collagen-induced platelet aggregation and no effect on bleeding time. In comparison, naproxen 500 mg daily suppressed collagen-induced platelet aggregation and significantly increased bleeding time.

GENERAL PRECAUTIONS SECTION.

General. Nabumetone tablets cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if decision is made to discontinue corticosteroids.The pharmacological activity of nabumetone tablets in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.. Hepatic Effects. Borderline elevations of or more liver function tests may occur in up to 15% of patients taking NSAIDs including Nabumetone tablets. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately 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. patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of more severe hepatic reaction while on therapy with nabumetone tablets. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), nabumetone tablets should be discontinued.. Hematological Effects. Anemia is sometimes seen in patients receiving NSAIDs, including nabumetone tablets. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including nabumetone tablets, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia.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. Patients receiving nabumetone tablets who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored (see CLINICAL PHARMACOLOGY, Special Studies, Other).. 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 non-steroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, nabumetone tablets should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.. Photosensitivity. Based on ultraviolet (U.V.) light photosensitivity testing, nabumetone may be associated with more reactions to sun exposure than might be expected based on skin tanning types.

INFORMATION FOR PATIENTS SECTION.

Information for Patients. 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.Nabumetone tablets, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS, Cardiovascular Effects).Nabumetone tablets, like other NSAIDs, 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, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative signs or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS, Gastrointestinal Effects Risk of Ulceration, Bleeding, and Perforation).Nabumetone tablets, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalization and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible.Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians.Patients should be informed 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, patients should be instructed to stop therapy and seek immediate medical therapy.Patients should be informed of the signs of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS).In late pregnancy, as with other NSAIDs, nabumetone tablets should be avoided because they may cause premature closure of the ductus arteriosus.. Nabumetone tablets, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS, Cardiovascular Effects).. Nabumetone tablets, like other NSAIDs, 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, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative signs or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS, Gastrointestinal Effects Risk of Ulceration, Bleeding, and Perforation).. Nabumetone tablets, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalization and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible.. Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians.. Patients should be informed 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, patients should be instructed to stop therapy and seek immediate medical therapy.. Patients should be informed of the signs of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS).. In late pregnancy, as with other NSAIDs, nabumetone tablets should be avoided because they may cause premature closure of the ductus arteriosus.

PHARMACOKINETICS SECTION.

Pharmacokinetics. After oral administration, approximately 80% of radiolabeled dose of nabumetone is found in the urine, indicating that Nabumetone is well absorbed from the gastrointestinal tract. Nabumetone itself is not detected in the plasma because, after absorption, it undergoes rapid biotransformation to the principal active metabolite, 6-methoxy-2-naphthylacetic acid (6MNA). Approximately 35% of 1,000 mg oral dose of nabumetone is converted to 6MNA and 50% is converted into unidentified metabolites which are subsequently excreted in the urine. Following oral administration of nabumetone, 6MNA exhibits pharmacokinetic characteristics that generally follow one-compartment model with first order input and first order elimination.6MNA is more than 99% bound to plasma proteins. The free fraction is dependent on total concentration of 6MNA and is proportional to dose over the range of 1,000 mg to 2,000 mg. It is 0.2% to 0.3% at concentrations typically achieved following administration of 1,000 mg of nabumetone and is approximately 0.6% to 0.8% of the total concentrations at steady state following daily administration of 2,000 mg.Steady-state plasma concentrations of 6MNA are slightly lower than predicted from single-dose data. This may result from the higher fraction of unbound 6MNA which undergoes greater hepatic clearance.Coadministration of food increases the rate of absorption and subsequent appearance of 6MNA in the plasma but does not affect the extent of conversion of nabumetone into 6MNA. Peak plasma concentrations of 6MNA are increased by approximately one third.Coadministration with an aluminum-containing antacid had no significant effect on the bioavailability of 6MNA.Table 1: Mean Pharmacokinetic Parameters of Nabumetone Active Metabolite (6MNA) at Steady State Following Oral Administration of 1,000 mg or 2,000 mg Doses of NabumetoneAbbreviation(units)Young AdultsMean +- SD1,000 mgn 31Young AdultsMean +- SD2,000 mgn 12ElderlyMean +- SD1,000 mgn 27 Tmax (hr) 3.0 (1.0 to 12.0) 2.5 (1.0 to 8.0) 4.0 (1.0 to 10.0) 1/2 (hr) 22.5 +- 3.7 26.2 +- 3.7 29.8 +- 8.1 CLss/F (mL/min) 26.1 +- 17.3 21.0 +- 4.0 18.6 +- 13.4 Vdss/F (L) 55.4 +- 26.4 53.4 +- 11.3 50.2 +- 25.3The simulated curves in the graph below illustrate the range of active metabolite plasma concentrations that would be expected from 95% of patients following 1,000 mg to 2,000 mg doses to steady state. The cross-hatched area represents the expected overlap in plasma concentrations due to intersubject variation following oral administration of 1,000 mg to 2,000 mg of nabumetone.Nabumetone Active Metabolite (6MNA) Plasma Concentrations at Steady State Following Once-Daily Dosing of Nabumetone 1,000 mg (n 31) 2,000 mg (n 12)6MNA undergoes biotransformation in the liver, producing inactive metabolites that are eliminated as both free metabolites and conjugates. None of the known metabolites of 6MNA has been detected in plasma. Preliminary in vivo and in vitro studies suggest that unlike other NSAIDs, there is no evidence of enterohepatic recirculation of the active metabolite. Approximately 75% of radiolabeled dose was recovered in urine in 48 hours. Approximately 80% was recovered in 168 hours. further 9% appeared in the feces. In the first 48 hours, metabolites consisted of: -nabumetone, unchanged not detectable -6-methoxy-2-naphthylacetic acid(6MNA), unchanged <1% -6MNA, conjugated 11% -6-hydroxy-2-naphthylacetic acid(6HNA), unchanged 5% -6HNA, conjugated 7% -4-(6-hydroxy-2-naphthyl)-butan-2-ol, Conjugated 9% -O-desmethyl-nabumetone, conjugated 7% -unidentified minor metabolites34% Total Dose: 73% Following oral administration of dosages of 1,000 mg to 2,000 mg to steady state, the mean plasma clearance of 6MNA is 20 to 30 mL/min and the elimination half-life is approximately 24 hours.. Figure. Elderly Patients. Steady-state plasma concentrations in elderly patients were generally higher than in young healthy subjects (see Table for summary of pharmacokinetic parameters).. Renal Insufficiency. In moderate renal insufficiency patients (creatinine clearance 30 to 49 mL/min), the terminal half-life of 6MNA was increased by approximately 50% (39.2 +- 7.8 hrs, = 12) compared to the normal subjects (26.9 +- 3.3 hrs, = 13), and there was 50% increase in the plasma levels of unbound 6MNA.Additionally, the renal excretion of 6MNA in the moderate renal impaired patients decreased on average by 33% compared to that in the normal patients. similar increase in the mean terminal half-life of 6MNA was seen in small study of patients with severe renal dysfunction (creatinine clearance 30 mL/min). In patients undergoing hemodialysis, steady-state plasma concentrations of the active metabolite 6MNA were similar to those observed in healthy subjects. Due to extensive protein binding, 6MNA is not dialyzable.Dosage adjustment of nabumetone generally is not necessary in patients with mild renal insufficiency (>= 50 mL/min). Caution should be used in prescribing nabumetone to patients with moderate or severe renal insufficiency. The maximum starting doses of nabumetone in patients with moderate or severe renal insufficiency should not exceed 750 mg or 500 mg, respectively once daily. Following careful monitoring of renal function in patients with moderate or severe renal insufficiency, daily doses may be increased to maximum of 1,500 mg and 1,000 mg, respectively (see WARNINGS, Renal Effects).. Hepatic Impairment. Data in patients with severe hepatic impairment are limited. Biotransformation of nabumetone to 6MNA and the further metabolism of 6MNA to inactive metabolites is dependent on hepatic function and could be reduced in patients with severe hepatic impairment (history of or biopsy-proven cirrhosis).

PRECAUTIONS SECTION.

PRECAUTIONS. General. Nabumetone tablets cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if decision is made to discontinue corticosteroids.The pharmacological activity of nabumetone tablets in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.. Hepatic Effects. Borderline elevations of or more liver function tests may occur in up to 15% of patients taking NSAIDs including Nabumetone tablets. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately 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. patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of more severe hepatic reaction while on therapy with nabumetone tablets. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), nabumetone tablets should be discontinued.. Hematological Effects. Anemia is sometimes seen in patients receiving NSAIDs, including nabumetone tablets. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including nabumetone tablets, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia.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. Patients receiving nabumetone tablets who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored (see CLINICAL PHARMACOLOGY, Special Studies, Other).. 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 non-steroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, nabumetone tablets should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.. Photosensitivity. Based on ultraviolet (U.V.) light photosensitivity testing, nabumetone may be associated with more reactions to sun exposure than might be expected based on skin tanning types.. Information for Patients. 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.Nabumetone tablets, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS, Cardiovascular Effects).Nabumetone tablets, like other NSAIDs, 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, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative signs or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS, Gastrointestinal Effects Risk of Ulceration, Bleeding, and Perforation).Nabumetone tablets, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalization and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible.Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians.Patients should be informed 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, patients should be instructed to stop therapy and seek immediate medical therapy.Patients should be informed of the signs of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS).In late pregnancy, as with other NSAIDs, nabumetone tablets should be avoided because they may cause premature closure of the ductus arteriosus.. Nabumetone tablets, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS, Cardiovascular Effects).. Nabumetone tablets, like other NSAIDs, 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, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative signs or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS, Gastrointestinal Effects Risk of Ulceration, Bleeding, and Perforation).. Nabumetone tablets, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalization and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible.. Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians.. Patients should be informed 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, patients should be instructed to stop therapy and seek immediate medical therapy.. Patients should be informed of the signs of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS).. In late pregnancy, as with other NSAIDs, nabumetone tablets should be avoided because they may cause premature closure of the ductus arteriosus.. Laboratory Tests. Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs, should have their CBC and chemistry profile checked periodically. 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, nabumetone tablets should be discontinued.. Drug Interactions. ACE-Inhibitors. Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors.. Aspirin. When nabumetone tablets are administered with aspirin, its protein binding is reduced, although the clearance of free nabumetone is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of nabumetone tablets and aspirin is not generally recommended because of the potential of increased adverse effects.. Diuretics. Clinical studies, as well as postmarketing observations, have shown that nabumetone tablets can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see WARNINGS, Renal Effects), as well as to assure diuretic efficacy. Lithium. NSAIDs have produced an elevation of plasma lithium levels and 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, subjects should be observed carefully for signs of lithium toxicity.. 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. Caution should be used when NSAIDs are administered concomitantly with methotrexate.. Warfarin. The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have risk of serious GI bleeding higher than users of either drug alone.In vitro studies have shown that, because of its affinity for protein, 6MNA may displace other protein-bound drugs from their binding site. Caution should be exercised when administering nabumetone tablets with warfarin since interactions have been seen with other NSAIDs.Concomitant administration of an aluminum-containing antacid had no significant effect on the bioavailability of 6MNA. When administered with food or milk, there is more rapid absorption; however, the total amount of 6MNA in the plasma is unchanged (see CLINICAL PHARMACOLOGY, Pharmacokinetics).. Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenesis, Mutagenesis. In year studies conducted in mice and rats, nabumetone had no statistically significant tumorigenic effect. Nabumetone did not show mutagenic potential in the Ames test and mouse micronucleus test in vivo; however, nabumetone- and 6MNA-treated lymphocytes in culture showed chromosomal aberrations at 80 mcg/mL and higher concentrations (equal to the average human exposure to nabumetone at the maximum recommended dose).. Impairment of Fertility. Nabumetone did not impair fertility of male or female rats treated orally at doses of 320 mg/kg/day (1,888 mg/m2) before mating.. Pregnancy. Teratogenic Effects. Pregnancy category C. Reproductive studies conducted in rats and rabbits have not demonstrated evidence of developmental abnormalities. However, animal reproduction studies are not always predictive of human response. There are no adequate, well-controlled studies in pregnant women. Nabumetone tablets should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.. Nonteratogenic Effects. Because of the known effects of non-steroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided.. Labor and Delivery. In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of nabumetone tablets on labor and delivery in pregnant women are unknown.. Nursing Mothers. It is not known whether this drug is excreted in human milk, however 6MNA is excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from nabumetone, decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.. Pediatric Use. Safety and effectiveness in pediatric patients have not been established.. Geriatric Use. As with any NSAIDs, caution should be exercised in treating the elderly (65 years and older). Of the 1,677 patients in U.S. clinical studies who were treated with nabumetone, 411 patients (24%) were 65 years or older; 22 patients (1%) were 75 years or older. No overall differences in efficacy or safety were observed between these older patients and younger ones. Similar results were observed in 1 year, non-U.S. postmarketing surveillance study of 10,800 patients treated with nabumetone, of whom 4,577 patients (42%) were 65 years or older.

SPL MEDGUIDE SECTION.

MEDICATION GUIDE. For Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)(See the end of this Medication Guide for list of prescription NSAID medicines.)What is the most important information should know about medicines called Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)NSAID medicines may increase the chance of heart attack or stroke that can lead to death. This chance increases: with longer use of NSAID medicines in people who have heart disease NSAID medicines should never be used right before or after heart surgery called coronary artery bypass graft (CABG).NSAID medicines can cause ulcers and bleeding in the stomach and intestines at any time during treatment. Ulcers and bleeding:can happen without warning symptoms may cause death The chance of person getting an ulcer or bleeding increases with:taking medicines called corticosteroids and anticoagulants longer use smoking drinking alcohol older age having poor health NSAID medicines should only be used:exactly as prescribed at the lowest dose possible for your treatment for the shortest time needed What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)NSAID medicines are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as: different types of arthritis menstrual cramps and other types of short-term pain Who should not take Non-Steroidal Anti-Inflammatory Drug (NSAID)Do not take an NSAID medicine:if you had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAID medicine for pain right before or after heart bypass surgery Tell your healthcare provider:about all of your medical conditions. about all of the medicines you take. NSAIDs and some other medicines can interact with each other and cause serious side effects. Keep list of your medicines to show to your healthcare provider and pharmacist. if you are pregnant. NSAID medicines should not be used by pregnant women late in their pregnancy. if you are breastfeeding. Talk to your doctor. What are the possible side effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)Serious side effects include:Other side effects include:heart attack stomach pain stroke constipation high blood pressure diarrhea heart failure from body swelling (fluid retention) gas heartburn kidney problems including kidney failure nausea bleeding and ulcers in the stomach and intestine vomiting low red blood cells (anemia) dizziness life-threatening skin reactions life-threatening allergic reactions liver problems including liver failure asthma attacks in people who have asthma Get emergency help right away if you have any of the following symptoms:shortness of breath or trouble breathing chest pain weakness in one part or side of your body slurred speech swelling of the face or throat Stop your NSAID medicine and call your healthcare provider right away if you have any of the following symptoms:nausea more tired or weaker than usual itching your skin or eyes look yellow stomach pain flu-like symptoms vomit blood there is blood in your bowel movement or it is black and sticky like tar unusual weight gain skin rash or blisters with fever swelling of the arms and legs, hands and feet These are not all the side effects with NSAID medicines. Talk to your healthcare provider or pharmacist for more information about NSAID medicines. Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.Other information about Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)Aspirin is an NSAID medicine but it does not increase the chance of heart attack. Aspirin can cause bleeding in the brain, stomach and intestines. Aspirin can also cause ulcers in the stomach and intestines. Some of these NSAID medicines are sold in lower doses without prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days. NSAID medicines that need prescription Vicoprofen contains the same dose of ibuprofen as over-the-counter (OTC) NSAIDs and is usually used for less than 10 days to treat pain. The OTC NSAID label warns that long term continuous use may increase the risk of heart attack or stroke. Generic NameTradename Celecoxib Celebrex Diclofenac Cataflam, Voltaren, Arthrotec (combined with misoprostol) Diflunisal Dolobid Etodolac Lodine, Lodine XL Fenoprofen Nalfon, Nalfon 200 Flurbiprofen Ansaid Ibuprofen Motrin, Tab-Profen, Vicoprofen (combined with hydrocodone), Combunox (combined with oxycodone) Indomethacin Indocin, Indocin SR, Indo-Lemmon, Indomethagan Ketoprofen Oruvail Ketorolac Toradol Mefenamic Acid Ponstel Meloxicam Mobic Nabumetone Relafen Naproxen Naprosyn, Anaprox, Anaprox DS, EC-Naproxyn, Naprelan, Naprapac (copackaged with lansoprazole) Oxaprozin Daypro Piroxicam Feldene Sulindac Clinoril Tolmetin Tolectin, Tolectin DS, Tolectin 600 This Medication Guide has been approved by the U.S. Food and Drug Administration.Manufactured by: Watson Pharma Private Ltd. Verna, Salcette Goa 403 722 INDIA Distributed by: Watson Pharma, Inc. Corona, CA 92880 USA Rev. date: 12/10. with longer use of NSAID medicines in people who have heart disease can happen without warning symptoms may cause death taking medicines called corticosteroids and anticoagulants longer use smoking drinking alcohol older age having poor health exactly as prescribed at the lowest dose possible for your treatment for the shortest time needed different types of arthritis menstrual cramps and other types of short-term pain if you had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAID medicine for pain right before or after heart bypass surgery about all of your medical conditions. about all of the medicines you take. NSAIDs and some other medicines can interact with each other and cause serious side effects. Keep list of your medicines to show to your healthcare provider and pharmacist. if you are pregnant. NSAID medicines should not be used by pregnant women late in their pregnancy. if you are breastfeeding. Talk to your doctor. heart attack stomach pain stroke constipation high blood pressure diarrhea heart failure from body swelling (fluid retention) gas heartburn kidney problems including kidney failure nausea bleeding and ulcers in the stomach and intestine vomiting low red blood cells (anemia) dizziness life-threatening skin reactions life-threatening allergic reactions liver problems including liver failure asthma attacks in people who have asthma shortness of breath or trouble breathing chest pain weakness in one part or side of your body slurred speech swelling of the face or throat nausea more tired or weaker than usual itching your skin or eyes look yellow stomach pain flu-like symptoms vomit blood there is blood in your bowel movement or it is black and sticky like tar unusual weight gain skin rash or blisters with fever swelling of the arms and legs, hands and feet Aspirin is an NSAID medicine but it does not increase the chance of heart attack. Aspirin can cause bleeding in the brain, stomach and intestines. Aspirin can also cause ulcers in the stomach and intestines. Some of these NSAID medicines are sold in lower doses without prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days.

WARNINGS SECTION.

WARNINGS. Cardiovascular Effects. Cardiovascular Thrombotic Events. Clinical trials of several COX-2 selective and nonselective NSAIDs of up to years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have 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, the lowest effective dose should be used 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. Patients should be informed about the signs and/or 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 does increase the risk of serious GI events (see WARNINGS, Gastrointestinal Effects Risk of Ulceration, Bleeding, and Perforation).Two large, controlled clinical trials of COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see CONTRAINDICATIONS).. Hypertension. NSAIDs, including nabumetone tablets, can lead to onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including nabumetone tablets, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy.. Congestive Heart Failure and Edema. Fluid retention and edema have been observed in some patients taking NSAIDs. Nabumetone tablets should be used with caution in patients with fluid retention or heart failure.. Gastrointestinal Effects Risk of Ulceration, Bleeding, and Perforation. NSAIDs, including nabumetone tablets, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the 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 in patients, who develop 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 to months, and in about to 4% of patients treated for year. These trends continue with longer duration of use, increasing the likelihood of developing serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk.In controlled clinical trials involving 1,677 patients treated with nabumetone (1,140 followed for year and 927 for years), the cumulative incidence of peptic ulcers was 0.3% (95% CI; 0%, 0.6%) at to months, 0.5% (95% CI; 0.1%, 0.9%) at year and 0.8% (95% CI; 0.3%, 1.3%) at years. In patients with active peptic ulcer, physicians must weigh the benefits of therapy with Nabumetone against possible hazards, institute an appropriate ulcer treatment regimen and monitor the patients progress carefully.NSAIDs should be prescribed with extreme caution in those with prior history of ulcer disease or gastrointestinal bleeding. Patients with prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have greater than 10 fold increased risk for developing 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 concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, 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, the lowest effective dose should be used 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 serious GI adverse event is suspected. This should include discontinuation of the NSAID until serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered.. Renal Effects. 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 compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID results in dose-dependent decrease in prostaglandin synthesis and, secondarily, in reduction of renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.. Advanced Renal Disease. No information is available from controlled clinical studies regarding the use of nabumetone tablets in patients with advanced renal disease. Therefore, treatment with nabumetone tablets is not recommended in these patients with advanced renal disease. If nabumetone tablet therapy must be initiated, close monitoring of the patients renal function is advisable.Because nabumetone undergoes extensive hepatic metabolism, no adjustment of the dosage of nabumetone is generally necessary in patients with mild renal insufficiency; however, as with all NSAIDs, patients with impaired renal function should be monitored more closely than patients with normal renal function (see CLINICAL PHARMACOLOGY, Pharmacokinetics, Renal Insufficiency). In subjects with moderate renal impairment (creatinine clearance 30 to 49 mL/min) there is 50% increase in unbound plasma 6MNA and dose adjustment may be warranted. The oxidized and conjugated metabolites of 6MNA are eliminated primarily by the kidneys.. Anaphylactoid Reactions. As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to nabumetone tablets. Nabumetone tablets should not be given to 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 and PRECAUTIONS, General, Preexisting Asthma). Emergency help should be sought in cases where an anaphylactoid reaction occurs.. Skin Reactions. NSAIDs, including nabumetone tablets, can cause serious skin adverse events 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 use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.. Pregnancy. In late pregnancy, as with other NSAIDs, nabumetone tablets should be avoided because it may cause premature closure of the ductus arteriosus.