nabumetone 750 MG Oral Tablet [Relafen]

INDICATIONS AND USAGE Carefully consider the potential benefits and risks of nabumetone tablets and other treatment options before deciding to use nabumetone tablets. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS ). Nabumetone tablets, USP are indicated: For relief of the signs and symptoms of rheumatoid arthritis. For relief of the signs and symptoms of osteoarthritis.

Dosage and Administration Section DOSAGE AND ADMINISTRATION Carefully consider the potential benefits and risks of nabumetone tablets and other treatment options before deciding to use nabumetone tablets. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS). After observing the response to initial therapy with nabumetone tablets, the dose and frequency should be adjusted to suit an individual patient’s needs. Osteoarthritis and Rheumatoid Arthritis: The recommended starting dose is 1,000 mg taken as a single dose with or without food. Some patients may obtain more symptomatic relief from 1,500 mg to 2,000 mg per day. Nabumetone tablets can be given in either a single or twice-daily dose. Dosages greater than 2,000 mg per day have not been studied. The lowest effective dose should be used for chronic treatment (see WARNINGS, RENAL EFFECTS). 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.

WARNINGS Cardiovascular Effects Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as 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

CONTRAINDICATIONS Nabumetone tablets are contraindicated in patients with known hypersensitivity to nabumetone or product excipients. Nabumetone tablets should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients (see WARNINGS, Anaphylactoid Reactions and PRECAUTIONS, General, Preexisting Asthma ). Nabumetone tablets are contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS ).

CLINICAL PHARMACOLOGY Nabumetone is a 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 a prodrug, which undergoes hepatic biotransformation to the active component, 6-methoxy-2-naphthylacetic acid (6MNA), that is a 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. Pharmacokinetics After oral administration, approximately 80% of a 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 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. 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 endoscopic