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Nabumetone (Tablet)

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Nabumetone (Tablet)
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Medication Guide for Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) (See the end of this Medication Guide for a list of prescription NSAID medicines.) What is the most important information I should know about medicines called Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)? NSAIDmedicines may increase the chance of a heart attack or stroke that can lead to death.This chance increases:with longer use of NSAID medicines NSAID medicines should never be used right before or after a heart surgery called a���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: The chance of a person getting an ulcer or bleeding increases with: NSAID medicines should only be used: 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: Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAIDs)? Do not take an NSAID medicine: Tell your healthcare provider: What are the possible side effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)? Get emergency help right away if you have any of the following symptoms: Stop your NSAID medicine and call your healthcare provider right away if you have any of the following symptoms: These are not all the side effects with NSAID medicines. Talk to your healthcare provider or pharmacist for more information about NSAID medicines. Other information about Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) NSAID medicines that need a prescription This Medication Guide has been approved by the U.S. Food and Drug Administration. Manufactured for: Par Pharmaceutical, Inc. , Spring Valley, NY 10977 By: Ivax Pharmaceuticals, Inc. Miami, Florida 33137
dailymed-instance:dosage
Carefully consider the potential benefits and risks of nabumetone and other treatment options before deciding to use nabumetone. 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, the dose and frequency should be adjusted to suit an individual patient's needs. Osteoarthritis and Rheumatoid Arthritis The recommended starting dose is 1000 mg taken as a single dose with or without food. Some patients may obtain more symptomatic relief from 1500 mg to 2000 mg per day. Nabumeton can be given in either a single or twice-daily dose. Dosages greater than 2000 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 1000 mg; therefore, after observing the response to initial therapy, the dose should be adjusted to meet individual patients' requirements.
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Nabumetone is a naphthylalkanone designated chemically as 4-(6-methoxy-2-naphthalenyl)-2-butanone. It has the following structure: Nabumetone is a white to off-white crystalline substance. It is nonacidic and practically insoluble in water, but soluble in alcohol and most organic solvents. It has an n-octanol:phosphate buffer partition coefficient of 2400 at pH 7.4. Each nabumetone tablet, for oral administration, contains 500 mg or 750 mg of nabumetone and has the following inactive ingredients: colloidal silicon dioxide, D&C yellow #10 aluminum lake, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium lauryl sulfate, sodium starch glycolate and titanium dioxide. In addition, the 750 mg contains FD&C yellow #6 aluminum lake.
dailymed-instance:clinicalP...
Nabumetone is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic and antipyretic properties in pharmacologic studies. As with other nonsteroidal 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. It is acidic and has an n-octanol:phosphate buffer partition coefficient of 0.5 at pH 7.4.<br/>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 1000 mg oral dose of nabumetone is converted to6MNA 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 1000 mg to 2000 mg. It is 0.2% to 0.3% at concentrations typically achieved following administration of nabumetone 1000 mg and is approximately 0.6% to 0.8% of the total concentrations at steady state following daily administration of 2000 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. The simulated curves in the graph below illustrate the range of active metabolite plasma concentrations that would be expected from 95% of patients following 1000 mg to 2000 mg doses to steady state. The cross-hatched area represents the expected overlap in plasma concentrations due to intersubject variation following oral administration of 1000 mg to 2000 mg of nabumetone. Nabumetone Active Metabolite (6MNA) Plasma Concentrations at Steady State Following Once-Daily Dosing of Nabumetone 1000 mg (n=31) 2000 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. Approximately75% 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: Following oral administration of dosages of 1000 mg to 2000 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 (creatine 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 1500 mg and 1000 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 utilizingCr-tagged red blood cells in healthy males showed no difference in fecal blood loss after 3 or 4 weeks' administration of 1000 mg or 2000 mg of nabumetone daily when compared to either placebo-treated or non-treated subjects. In contrast, aspirin 3600 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 1000 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 1000 mg or 2000 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 1000 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 1000 mg of nabumetone daily to ibuprofen 2400 mg/day and ibuprofen 2400 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, 1000 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.
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Nabumetone tablets are contraindicated in patients with known hypersensitivity to nabumetone or its excipients. Nabumetone 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, 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).
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Nabumetone Tablets are available as light yellow, oval shaped, film coated, unscored tablets, debossed���double triangle������4098���on one side and���500���on the other side containing 500 mg of nabumetone, packaged in bottles of 100 (NDC 49884-649-01) and 500 (NDC 49884-649-05) tablets. Nabumetone Tablets are available as dark yellow, oval shaped, film coated, unscored tablets, debossed���double triangle������4099���on one side and���750���on the other side containing 750 mg of nabumetone, packaged in bottles of 100 (NDC 49884-650-01) and 500 (NDC 49884-650-05) tablets. PHARMACIST: Dispense in a well-closed, light-resistant container as defined in the USP. Use child-resistant closure (as required). Important:Use safety closures when dispensing this product unless otherwise directed by physician or requested by purchaser. Store at 25��C (77��F); excursions permitted to 15���30��C (59-86��F) in well-closed container; dispense in light resistant container.
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Symptoms following acute NSAIDs overdoses are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression and coma may occur, but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose. Patients should be managed by symptomatic and supportive care following a NSAIDs overdose. There are no specific antidotes. Emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams/kg in children) and/or osmotic cathartic may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large overdose (5 to 10 times the usual dose). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. There have been overdoses of up to 25 grams of nabumetone reported with no long-term sequelae following standard emergency treatment (i.e., activated charcoal, gastric lavage, IV H2-blockers, etc.).
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Nabumetone
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Nabumetone (Tablet)
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Adverse reaction information was derived from blinded-controlled and open-labeled clinical trials and from world-wide 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 1 month, 1,327 for at least 3 months, 929 for at least a year and 750 for at least 2 years. More than 300 patients have been treated for 5 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 Gastrointestinal:diarrhea (14%), dyspepsia (13%), abdominal pain (12%), constipation*, flatulence*, nausea*, positive stool guaiac*, dry mouth, gastritis, stomatitis, vomiting Central Nervous System:dizziness*, headache*, fatigue, increased sweating, insomnia, nervousness, somnolence Dermatologic:pruritus*, rash* Special Senses:tinnitus* Miscellaneous: edema* _________________________________________________________________________________________ *Incidence of reported reaction between 3% and 9%. Reactions occurring in 1% to 3% of the patients are unmarked. Incidence<1% - Probably Causally Related 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 ________________________________________________________________________________________ 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
dailymed-instance:warning
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, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, 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 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 (see CONTRAINDICATIONS). Hypertension NSAIDs, including nabumetone, can lead to onset of new hypertension or worsening of pre-existing 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, 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 should be used with caution in patients with fluid retention or heart failure.<br/>Gastrointestinal Effects: Risk of Ulceration, Bleeding and Perforation: NSAIDs, including nabumetone, 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 one in five patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. These trends continue with longer durationof 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 trial 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 5 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 gastro- intestinal 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 typically followed by recovery to the pretreatment state. Advanced Renal Disease No information is available from controlled clinical studies regarding the use of nabumetone in patients with advanced renal disease. Therefore, treatment with nabumetone is not recommended in these patients with advanced renal disease. If nabumetone 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 49mL/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. Nabumetone 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, Preexisting Asthma). Emergency help should be sought in cases where an anaphylactoid reaction occurs. SkinReactions NSAIDs, including nabumetone, 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 should be avoided because it may cause premature closure of the ductus arteriosus.
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Carefully consider the potential benefits and risks of nabumetone and other treatment options before deciding to use nabumetone. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS). Nabumetone tablets are indicated for relief of signs and symptoms of osteoarthritis and rheumatoid arthritis.
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Nabumetone