s , renal effects ), as well as to assure diuretic efficacy. lithium nsaids 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, 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 a 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 ).

nimize the potential risk for an adverse cv event in nsaid-treated patients, use the lowest effective dose for the shortest duration possible. physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous cv symptoms. patients should be informed about the symptoms of serious cv events and the steps to take if they occur. there is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious cv thrombotic events associated with nsaid use. the concurrent use of aspirin and an nsaid, such as nabumetone, increases the risk of serious gastrointestinal (gi) events [ see warnings ]. status post coronary artery bypass graft (cabg) surgery two large, controlled clinical trials of a cox-2 selective nsaid for the treatment of pain in the first 10–14 days following cabg surgery found an increased incidence of myocardial infarction and stroke. nsaids are contraindicated in the setting of cabg [ see contraindications ]. post-mi patients observational studies conducted in the danish national registry have demonstrated that patients treated with nsaids in the post-mi period were at increased risk of reinfarction, cv-related death, and all-cause mortality beginning in the first week of treatment. in this same cohort, the incidence of death in the first year post mi was 20 per 100 person years in nsaid-treated patients compared to 12 per 100 person years in non-nsaid exposed patients. although the absolute rate of death declined somewhat after the first year post-mi, the increased relative risk of death in nsaid users persisted over at least the next four years of follow-up. avoid the use of nabumetone tablets in patients with a recent mi unless the benefits are expected to outweigh the risk of recurrent cv thrombotic events. if nabumetone tablets are used in patients with a recent mi, monitor patients for signs of cardiac ischemia. 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. heart failure and edema the coxib and traditional nsaid trialists’ collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in cox-2 selective-treated patients and nonselective nsaid-treated patients compared to placebo-treated patients. in a danish national registry study of patients with heart failure, nsaid use increased the risk of mi, hospitalization for heart failure, and death. additionally, fluid retention and edema have been observed in some patients treated with nsaids. use of nabumetone may blunt the cv effects of several therapeutic agents used to treat these medical conditions [e.g., diuretics, ace inhibitors, or angiotensin receptor blockers (arbs)] [ see drug interactions ]. avoid the use of nabumetone tablets in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. if nabumetone tablets are used in patients with severe heart failure, monitor patients for signs of worsening 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 1 in 5 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 to 6 months, and in about 2 to 4% of patients treated for 1 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 therapy is not without risk. in controlled clinical trials involving 1,677 patients treated with nabumetone (1,140 followed for 1 year and 927 for 2 years), the cumulative incidence of peptic ulcers was 0.3% (95% ci; 0%, 0.6%) at 3 to 6 months, 0.5% (95% ci; 0.1%, 0.9%) at 1 year and 0.8% (95% ci; 0.3%, 1.3%) at 2 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 a prior history of ulcer disease or gastrointestinal bleeding. patients with a prior history of peptic ulcer disease and/or gastrointestinal 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 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 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, 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 a compensatory role in the maintenance of renal perfusion. in these patients, administration of an nsaid results in a dose-dependent decrease in prostaglandin synthesis and, secondarily, in a 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 patient's 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 a 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. drug reaction with eosinophilia and systemic symptoms (dress) drug reaction with eosinophilia and systemic symptoms (dress) has been reported in patients taking nsaids such as nabumetone tablets. some of these events have been fatal or life-threatening. dress typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. sometimes symptoms of dress may resemble an acute viral infection. eosinophilia is often present. because this disorder is variable in its presentation, other organ systems not noted here may be involved. it is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. if such signs or symptoms are present, discontinue nabumetone tablets and evaluate the patient immediately. fetal toxicity premature closure of fetal ductus arteriosus : avoid use of nsaids, including nabumetone tablets, in pregnant women at about 30 weeks gestation and later. nsaids including nabumetone tablets, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. oligohydramnios/neonatal renal impairment : use of nsaids, including nabumetone tablets, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. these adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after nsaid initiation. oligohydramnios is often, but not always, reversible with treatment discontinuation. complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. in some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. if nsaid treatment is necessary between about 20 weeks and 30 weeks gestation, limit nabumetone tablets use to the lowest effective dose and shortest duration possible. consider ultrasound monitoring of amniotic fluid if nabumetone tablets treatment extends beyond 48 hours. discontinue nabumetone tablets if oligohydramnios occurs and follow up according to clinical practice (see precautions , pregnancy ) .

are 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 an abnormal liver test has occurred, should be evaluated for evidence of the development of a 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.

the response to initial therapy, the dose should be adjusted to meet individual patients' requirements.

*2 , headache *2 , fatigue, increased sweating, insomnia, nervousness, somnolence. dermatologic pruritus *2 , rash *2 . special senses tinnitus *2 . miscellaneous edema *2 . * 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 gastrointestinal anorexia, jaundice, duodenal ulcer, dysphagia, gastric ulcer, gastroenteritis, gastrointestinal bleeding, increased appetite, liver function abnormalities, melena, hepatic failure . central nervous system asthenia, agitation, anxiety, confusion, depression, malaise, paresthesia, tremor, vertigo. dermatologic bullous eruptions, photosensitivity, urticaria, pseudoporphyria cutanea tarda, toxic epidermal necrolysis , erythema multiforme, stevens-johnson syndrome. cardiovascular vasculitis. metabolic weight gain. respiratory dyspnea, eosinophilic pneumonia , hypersensitivity pneumonitis , idiopathic interstitial pneumonitis. genitourinary albuminuria, azotemia, hyperuricemia , interstitial nephritis , nephrotic syndrome , vaginal bleeding , renal failure . special senses abnormal vision. hematologic/lymphatic thrombocytopenia. hypersensitivity anaphylactoid 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 gastrointestinal bilirubinuria, duodenitis, eructation, gallstones, gingivitis, glossitis, pancreatitis, rectal bleeding. central nervous system nightmares. dermatologic acne, alopecia. cardiovascular angina, arrhythmia, hypertension, myocardial infarction, palpitations, syncope, thrombophlebitis. respiratory asthma, cough. genitourinary dysuria, hematuria, impotence, renal stones. special senses taste disorder. body as a whole fever, chills. hematologic/lymphatic anemia, leukopenia, granulocytopenia. metabolic/nutritional hyperglycemia, hypokalemia, weight loss. to report suspected adverse reactions, contact teva at 1-888-838-2872 or fda at 1-800-fda-1088 or http://www.fda.gov/medwatch for voluntary reporting of adverse reactions.

s , renal effects ), as well as to assure diuretic efficacy. lithium nsaids 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, 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 a 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 ).

nction, invasive procedures such as exchange transfusion or dialysis were required. if nsaid treatment is necessary between about 20 weeks and 30 weeks gestation, limit nabumetone tablets use to the lowest effective dose and shortest duration possible. consider ultrasound monitoring of amniotic fluid if nabumetone tablets treatment extends beyond 48 hours. discontinue nabumetone tablets if oligohydramnios occurs and follow up according to clinical practice (see precautions , pregnancy ) .

id use in women in the first or second trimesters of pregnancy are inconclusive. in animal reproduction studies conducted in rats and rabbits, studies have not demonstrated evidence of developmental abnormalities. however, animal reproduction studies are not always predictive of human response. based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. in animal studies, administration of prostaglandin synthesis inhibitors such as nabumetone, resulted in increased pre- and post-implantation loss. prostaglandins also have been shown to have an important role in fetal kidney development. in published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. the estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. clinical considerations fetal/neonatal adverse reactions premature closure of fetal ductus arteriosus: avoid use of nsaids in women at about 30 weeks gestation and later in pregnancy, because nsaids, including nabumetone tablets, can cause premature closure of the fetal ductus arteriosus (see warnings , fetal toxicity ). oligohydramnios/neonatal renal impairment if an nsaid is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. if nabumetone tablet treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. if oligohydramnios occurs, discontinue nabumetone tablets and follow up according to clinical practice (see warnings , fetal toxicity ). data human data 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. premature closure of fetal ductus arteriosus: published literature reports that the use of nsaids at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. oligohydramnios/neonatal renal impairment: published studies and postmarketing reports describe maternal nsaid use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. these adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after nsaid initiation. in many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. there have been a limited number of case reports of maternal nsaid use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. these limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal nsaid use. because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to nsaids through maternal use is uncertain.

transformation to the principal active metabolite, 6-methoxy-2-naphthylacetic acid (6mna). approximately 35% of a 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 a 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 nabumetone abbreviation (units) young adults mean ± sd 1,000 mg n = 31 young adults mean ± sd 2,000 mg n = 12 elderly mean ± sd 1,000 mg n = 27 t max (hr) 3.0 (1.0 to 12.0) 2.5 (1.0 to 8.0) 4.0 (1.0 to 10.0) t ½ (hr) 22.5 ± 3.7 26.2 ± 3.7 29.8 ± 8.1 cl ss /f (ml/min) 26.1 ± 17.3 21.0 ± 4.0 18.6 ± 13.4 vd ss /f (l) 55.4 ± 26.4 53.4 ± 11.3 50.2 ± 25.3 the 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 a radiolabeled dose was recovered in urine in 48 hours. approximately 80% was recovered in 168 hours. a 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 metabolites 34% 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 1 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, n = 12) compared to the normal subjects (26.9 ± 3.3 hrs, n = 13), and there was a 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. a similar increase in the mean terminal half-life of 6mna was seen in a 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 a 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 51 cr-tagged red blood cells in healthy males showed no difference in fecal blood loss after 3 or 4 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 5 clinical trials that compared a total of 194 patients on 1,000 mg of nabumetone daily or naproxen 250 mg or 500 mg twice daily for 3 to 12 weeks, treatment with nabumetone resulted in fewer patients with endoscopically detected lesions (> 3 mm). in 2 trials a total of 101 patients administered 1,000 mg or 2,000 mg of nabumetone daily or piroxicam 10 mg to 20 mg for 7 to 10 days, there were fewer patients treated with nabumetone with endoscopically detected lesions. in 3 trials of a total of 47 patients on 1,000 mg of nabumetone daily or indomethacin 100 mg to 150 mg daily for 3 to 4 weeks, the endoscopy scores were higher with indomethacin. another 12 week trial in a 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 a lower number of endoscopically detected lesions (> 5 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 1 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.

stration 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 nabumetone abbreviation (units) young adults mean ± sd 1,000 mg n = 31 young adults mean ± sd 2,000 mg n = 12 elderly mean ± sd 1,000 mg n = 27 t max (hr) 3.0 (1.0 to 12.0) 2.5 (1.0 to 8.0) 4.0 (1.0 to 10.0) t ½ (hr) 22.5 ± 3.7 26.2 ± 3.7 29.8 ± 8.1 cl ss /f (ml/min) 26.1 ± 17.3 21.0 ± 4.0 18.6 ± 13.4 vd ss /f (l) 55.4 ± 26.4 53.4 ± 11.3 50.2 ± 25.3 the 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 a radiolabeled dose was recovered in urine in 48 hours. approximately 80% was recovered in 168 hours. a 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 metabolites 34% 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 1 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, n = 12) compared to the normal subjects (26.9 ± 3.3 hrs, n = 13), and there was a 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. a similar increase in the mean terminal half-life of 6mna was seen in a 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 a 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).

matoid arthritis patients, most patients responded to nabumetone in doses of 1,000 mg/day administered nightly; total daily dosages up to 2,000 mg were used. in open-labeled studies, 1,490 patients were permitted dosage increases and were followed for approximately 1 year (mode). twenty percent of patients (n = 294) were withdrawn for lack of effectiveness during the first year of these open-labeled studies. the following table provides patient-exposure to doses used in the u.s. clinical trials: table 2: clinical double-blinded and open-labeled trials of nabumetone in osteoarthritis and rheumatoid arthritis dose of nabumetone number of patients mean/mode duration of treatment (yr) oa ra oa ra 500 mg 17 6 0.4/– 0.2/– 1,000 mg 917 701 1.2/1 1.4/1 1,500 mg 645 224 2.3/1 1.7/1 2,000 mg 15 100 0.6/1 1.3/1 as with other nsaids, the lowest dose should be sought for each patient. patients weighing under 50 kg may be less likely to require dosages beyond 1,000 mg; therefore, after observing the response to initial therapy, the dose should be adjusted to meet individual patients' requirements.

verna, salcette goa 403 722 india manufactured for: teva pharmaceuticals parsippany, nj 07054 rev. d 2/2022

r 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 ). serious skin reactions, including dress advise patients to stop taking nabumetone tablets immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible (see warnings ). heart failure and edema advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [ see warnings ]. 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 ). fetal toxicity inform pregnant women to avoid use of nabumetone tablets and other nsaids starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. if treatment with nabumetone tablets is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours (see warnings , fetal toxicity and precautions , pregnancy ) .