August 12, 1998
November 14, 2008
APO-NABUMETONE Product Monograph Page 1 of 28
Table of Contents
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SUMMARY PRODUCT INFORMATION ......................................................... 3 INDICATIONS AND CLINICAL USE ............................................................... 3 CONTRAINDICATIONS .................................................................................... 3 WARNINGS AND PRECAUTIONS................................................................... 4 ADVERSE REACTIONS..................................................................................... 9 DRUG INTERACTIONS ..................................................................................... 12 DOSAGE AND ADMINISTRATION ................................................................. 13 OVERDOSAGE ................................................................................................... 13 ACTION AND CLINICAL PHARMACOLOGY ............................................... 13 STORAGE AND STABILITY............................................................................. 15 DOSAGE FORMS, COMPOSITION AND PACKAGING ................................ 15
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PHARMACEUTICAL INFORMATION............................................................. 16 CLINICAL TRIALS ............................................................................................. 17 DETAILED PHARMACOLOGY ........................................................................ 18 TOXICOLOGY .................................................................................................... 19 REFERENCES .................................................................................................... 23
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| Route of Administration | Dosage Form / Strength | Clinically Relevant Nonmedicinal Ingredients |
| Oral | Tablet/500 mg | For a complete listing see Dosage Forms, Composition and Packaging section. |
APO-NABUMETONE (Nabumetone Tablets) is indicated for acute and chronic relief of the signs and symptoms of rheumatoid arthritis and osteoarthritis.
Geriatrics (>=65 years of age)
Patients older than 65 years and frail or debilitated patients are most susceptible to a variety of adverse reactions from nonsteroidal anti-inflammatory drugs (NSAIDs) and a brief discussion can be found under WARNINGS AND PRECAUTIONS.
Pediatrics
No clinical data is available.
Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing of ingredients, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the product monograph.
Patients who have previously exhibited hypersensitivity to it or other nonsteroidal anti- inflammatory drugs. The potential for cross-reactivity between different NSAIDs must be kept in mind.
Patients with active peptic ulcer, a history of recurrent ulceration or active inflammatory disease of the gastrointestinal system.
Patients with severely impaired or deteriorating renal function. Individuals with lesser degrees of renal impairment are at risk of deterioration of their renal function when
prescribed NSAIDs and must be monitored. See WARNINGS AND PRECAUTIONS, Renal.
APO-NABUMETONE (Nabumetone Tablets) should not be given to patients with the complete or partial syndrome of nasal polyps, or in whom ASA or other NSAIDs induce asthma, rhinitis, urticaria or other allergic type reactions. Fatal anaphylactoid reactions have occurred in such individuals. As well, individuals with the above medical problems are at risk of a severe reaction even if they have taken NSAIDs in the past without any adverse effects.
Patients with significant hepatic impairment or active liver disease.
APO-NABUMETONE is not recommended for use with other NSAIDs because of the absence of any evidence demonstrating synergistic benefits and the potential for additive side effects.
General
In occasional cases, with some NSAIDs, the symptoms of aseptic meningitis (stiff neck, severe headaches, nausea and vomiting, fever or clouding of consciousness) have been observed. Patients with autoimmune disorders (systemic lupus erythematosus, mixed connective tissues diseases, etc.) seem to be predisposed. Although aseptic meningitis has not been reported for nabumetone tablets, in such patients, the physician must be vigilant to the potential development of this complication.
In common with other anti inflammatory drugs, nabumetone may mask the usual signs of infection.
Carcinogenesis and Mutagenesis
See PART II: SCIENTIFIC INFORMATION, TOXICOLOGY.
Cardiovascular
Fluid retention and edema have been observed in patients treated with nabumetone. Therefore, as with many other NSAIDs, the possibility of precipitating congestive heart failure in elderly patients or those with compromised cardiac function should be borne in mind. Nabumetone should be used with caution in patients with heart failure, hypertension or other conditions predisposing to fluid retention. With NSAID treatment, there is a potential risk of hyperkalemia particularly in patients with conditions such as diabetes mellitus or renal failure; elderly patients; or in patients receiving concomitant therapy with beta adrenergic blockers, angiotensin converting enzyme inhibitors or some diuretics. Serum electrolytes should be monitored periodically during long-term therapy, especially in those patients at risk.
Gastrointestinal
Peptic ulceration, perforation and gastrointestinal (GI) bleeding, sometimes severe and occasionally fatal can occur at any time, with or without symptoms during therapy with NSAIDs including nabumetone. Although minor upper GI problems, such as dyspepsia, are common, usually developing early in therapy, physicians should remain alert for ulceration and bleeding in patients treated chronically with nonsteroidal anti-inflammatory drugs, even in the absence of previous GI tract symptoms. Nabumetone should be given under close medical supervision to patients prone to gastrointestinal irritation particularly those with a history of peptic ulcer, diverticulosis or other inflammatory disease of the gastrointestinal tract such as ulcerative colitis and Crohn's disease. In these cases the physician must weigh the benefits of treatment against the possible hazards. In controlled and open label extension 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. Physicians should inform patients about the signs and/or symptoms of serious GI toxicity and instruct them to contact a physician immediately if they experience persistent dyspepsia or other symptoms or signs suggestive of gastrointestinal ulceration or bleeding. Because serious GI tract ulceration and bleeding can occur without warning symptoms, physicians should follow chronically treated patients by checking their hemoglobin periodically and by being vigilant for the signs and symptoms of ulceration and bleeding and should inform the patient of the importance of this follow-up. If ulceration is suspected or confirmed, or if GI bleeding occurs, nabumetone should be discontinued immediately, appropriate treatment instituted and the patient monitored closely. Studies to date have identified that there is no group of patients not at risk of developing ulceration and bleeding. A prior history of serious GI events and other factors such as excess alcohol intake, smoking, age, female gender and anticoagulant use have been associated with increased risk. Caution should be used when administering to patients with other therapies known to increase the risk of gastrointestinal ulcer (e.g., oral corticosteroids). High doses of any NSAID may carry a greater risk of these reactions, although controlled clinical trials showing this do not exist in most cases. In considering the use of relatively large doses (within the recommended dosage range), sufficient benefit should be anticipated to offset the potential increased risk of GI toxicity. Patients older than 65 years and frail or debilitated patients are most susceptible to a variety of adverse reactions from NSAIDs: the incidence of these adverse reactions generally increases with dose and duration of treatment. In addition, these patients are less tolerant to ulceration and bleeding. Most reports of fatal GI events are in this population. Older patients are also at risk of lower esophageal ulceration and bleeding. However, data from controlled clinical studies with nabumetone (where 24% of 1677 patients were >=65 years of age) have indicated that there were no overall differences in efficacy or safety between older patients and younger ones. As with other NSAIDs, the lowest dose should be sought for each patient. Therefore, after observing the response to initial therapy, the dose should be adjusted to meet individual patients' requirements. There is no definitive evidence that the concomitant administration of histamine H2 receptor antagonists and/or antacids will either prevent the occurrence of gastrointestinal side effects or allow continuation of nabumetone therapy when and if these adverse reactions occur.
Genitourinary
Some NSAIDs are known to cause persistent urinary symptoms (bladder pain, dysuria, urinary frequency), hematuria or cystitis. The onset of these symptoms may occur at any time after the initiation of therapy with an NSAID. Some cases have become severe on continued treatment. Should urinary symptoms occur, treatment with nabumetone must be stopped immediately to obtain recovery. This should be done before any urological investigations or treatments are carried out.
Hematologic
Drugs inhibiting prostaglandin biosynthesis do interfere with platelet function to varying degrees; therefore, patients who may be adversely affected by such an action should be carefully observed when nabumetone is administered. Blood dyscrasias (such as neutropenia, leukopenia, thrombocytopenia, aplastic anemia and agranulocytosis) associated with the use of NSAIDs are rare, but could have severe consequences. In one week repeat dose studies in healthy volunteers, nabumetone 1000 mg daily had little effect on collagen induced platelet aggregation and no effect on bleeding time. Nabumetone cannot be used as a substitute for low dose aspirin therapy in patients requiring such therapy.
Hepatic/Biliary/Pancreatic
As with other NSAIDs, borderline elevations of one or more liver tests may occur in up to 15% of patients. These abnormalities may progress, may remain essentially unchanged, or may return to normal with continued therapy. The ALT (SGPT) test is probably the most sensitive indicator of liver dysfunction. Meaningful (3 times the upper limit of normal) elevations of ALT (SGPT) or AST (SGOT) have occurred in controlled clinical trials of nabumetone in less than 1% of patients. 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 more severe hepatic reaction while on therapy with this drug. Severe hepatic reactions, including jaundice and cases of fatal hepatitis have been reported with NSAIDs. Although such reactions are rare, if abnormal liver tests persist or worsen, if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc. ), this drug should be discontinued. During long-term therapy, liver function tests should be monitored periodically. If there is a need to prescribe this drug in the presence of impaired liver function, it must be done under strict observation.
Immune
Patients sensitive to any one of the nonsteroidal anti-inflammatory drugs may be sensitive to any of the other NSAIDs also.
As with other NSAIDs, allergic reactions may occur. Manifestations of allergic reactions include urticaria, dyspnea, and in rare instances anaphylaxis, or severe skin reactions such as Stevens- Johnson syndrome.
Neurologic
Some patients may experience drowsiness, dizziness, vertigo, insomnia, or depression with the use of nabumetone. Patients experiencing these side effects should exercise caution in carrying out activities that require alertness.
Ophthalmologic
Blurred and/or diminished vision has been reported with the use of nabumetone and other NSAIDs. If such symptoms develop this drug should be discontinued and an ophthalmologic examination performed; ophthalmic examinations should be carried out at periodic intervals in any patients receiving this drug for an extended period of time.
Renal
Long-term administration of NSAIDs to animals has resulted in renal papillary necrosis and other abnormal renal pathology. In humans, there have been reports of acute interstitial nephritis with hematuria, proteinuria, and occasionally nephrotic syndrome associated with NSAID use. A second form of renal toxicity has been seen in patients with pre-renal conditions leading to the reduction in renal blood flow or blood volume, where the renal prostaglandins have a supportive role in the maintenance of renal perfusion. In these patients, administration of a NSAID may cause a dose-dependent reduction in prostaglandin formation and 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 nonsteroidal anti-inflammatory therapy is usually followed by recovery to the pre-treatment state. Nabumetone and its metabolites are eliminated primarily by the kidneys, therefore the drug should be used with caution in patients with impaired renal function. As with other NSAIDs, in patients with severely impaired renal function (creatinine clearance <30 mL/min or <0.5 mL/sec), lower doses of nabumetone should be considered and patients should be monitored more closely than patients with normal renal function. Laboratory tests should be performed at baseline and within weeks of starting therapy. Further tests should be carried out as necessary: if the impairment worsens, discontinuation of therapy may be warranted. In moderate renal impairment (creatinine clearance 30 to 49 mL/min) there is a 50% increase in unbound plasma 6-MNA and dose reduction may be warranted (see DRUG INTERACTIONS). During long-term therapy, kidney function should be monitored periodically.
Special Populations
There is no clinical trial experience with the use of nabumetone during human pregnancy. Use of nabumetone during the first two trimesters of pregnancy should be restricted to situations where the potential benefit to the mother justifies the potential risk to the fetus or nursing infant. The known effects of drugs of this class on the human fetus during the third trimester of pregnancy include constriction of the ductus arteriosis, pulmonary and cardiac changes. Therefore, use of nabumetone during the third trimester of pregnancy is not recommended. Teratogenic effects were not observed in rats or rabbits. Postnatal development was not affected even though the active metabolite of nabumetone (6-MNA) is found in the milk of lactating rats. Nabumetone and/or its active metabolites have been shown to cross the placental barrier of rats. (See TOXICOLOGY).
There is no clinical trial experience with the use of nabumetone during human lactation. As the safety and efficacy of nabumetone in human lactation have not been established, its use is therefore not recommended.
Nabumetone is not recommended for use in children because the safety and efficacy in children have not been established.
Use in the elderly and debilitated patient should be monitored more closely as NSAID use in this population is known to be associated with a higher risk of adverse events. Data from controlled clinical studies (where 24% of 1677 patients were >=65 years of age) and UK post marketing studies with nabumetone (where 43% of 10,800 patients were >=65 years of age) indicate that there were no differences in efficacy or safety between older and younger patients. (See Cardiovascular, Gastrointestinal and Renal).
Clinical Trial Adverse Drug Reactions
Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
The most common adverse reactions encountered with NSAIDs are gastrointestinal, of which peptic ulcer, with or without bleeding, is the most severe. Fatalities have occurred particularly in the elderly. Adverse reaction information was derived from blinded controlled and open-labelled clinical trials and from worldwide marketing experience. Over 6,000 patients have been treated with nabumetone in clinical trials, and over 49,000 patients included in post-marketing surveillance studies and nabumetone has been prescribed extensively in those countries where the drug has received registration clearance. In large scale post-marketing studies the adverse event profile was highly consistent with the profile seen in clinical trials of nabumetone. The pattern of adverse events remained similar in patients treated with nabumetone for several years, similar in patients taking 1-2 g doses, and was similar in patients aged <65 or >=65 years. Information on adverse experiences observed in U.S. clinical studies is presented below. Of the 1,677 patients who received nabumetone during U.S. clinical trials, 1,524 were treated for at least one month, 1,327 for at least three months, 929 for at least a year and 750 for at least two years. Over 300 patients have been treated for five years or longer. The most frequently reported adverse reactions were related to the gastrointestinal tract. They were diarrhea, dyspepsia and abdominal pain. Discontinuation of therapy due to these adverse events was 1.3% (diarrhea), 0.8% (dyspepsia) and 1.1 % (abdominal pain) during the double blind phase of the US clinical trials involving 930 patients treated with nabumetone for up to 6 months. Of 1,677 patients treated with nabumetone in controlled and open label extension clinical trials (1,140 followed for one year and 927 for two years), the cumulative incidence of peptic ulcers was 0.3% at 3-6 months, 0.5% at one year and 0.8% at two years. The following table displays adverse events reported in long-term clinical trial follow-up involving treatment for up to 8 years. Where available, percentages are based upon the total number of observations, thus patients reporting multiple incidents of an adverse event have been recorded for each occurrence. Causal relationship to nabumetone has not necessarily been established for all of the events listed below.
Table 1 - Adverse Events Reported in Long-term Follow-up with Nabumetone
| Nabumetone (%) | |
| Gastrointestinal: | 14 |
| Diarrhea | |
| Dyspepsia | 13 |
| Abdominal Plain | 12 |
| Nausea | 9 |
| Flatulence | 6 |
| Constipation | 4 |
| Positive Stool Guaiac | 2 |
| Dry Mouth | 2 |
| Gastritis | 1 |
| Vomiting | 1 |
| Melena | 1 |
| Central Nervous System: | |
| Headache | 8 |
| Dizziness | 6 |
| Insomnia | 3 |
| Fatigue | 2 |
| Somnolence | 2 |
| Increased Sweating | 1 |
| Nervousness | 1 |
| Dermatologic: | |
| Rash | 7 |
| Pruritus | 4 |
| Special Senses: | |
| Tinnitus | 4 |
| Abnormal Vision | 2 |
| Cardiovascular: | |
| Hypertension | 1.7 |
| Palpitations | 1 |
| Respiratory: | |
| Dyspnea | 1 |
Less Common Clinical Trial Adverse Drug Reactions (<1%)
The following adverse events were reported in long-term clinical trial follow-up involving treatment for up to 8 years. Adverse events listed at an estimated incidence of <=0.01% are based on spontaneous reports from worldwide marketing experience. Where available, percentages are based upon the total number of observations, thus patients reporting multiple incidents of an adverse event have been recorded for each occurrence. Causal relationship to nabumetone has not necessarily been established for all of the events listed below.
Gastrointestinal
Eructation (0.7%), gastroenteritis (0.7%), anorexia (0.7%), rectal bleeding (0.5%), gastric ulcer (0.4%), duodenal ulcer (0.4%), stomatitis (0.4%), dysphagia (0.3%), increased appetite (0.2%), glossitis (0.2%), pancreatitis (0.1%), gingivitis (0.1%), duodenitis (0.1%), bilirubinuria (0.1%), gastrointestinal bleeding (0.1%), cholestatic jaundice (<=0.01%), gallstones (<=0.01%).
Central Nervous System
Depression (0.9%), vertigo (0.9%), malaise (0.8%), paresthesia (0.8%), asthenia (0.7%), anxiety (0.4%), confusion (0.3%), agitation (0.1%), tremor (0.1%), nightmares (<0.01%).
Dermatologic
Alopecia (0.9%), urticaria (0.7%), acne (0.4%), bullous eruptions (0.2%), photosensitivity (0.2%), pseudoporphyria cutanea tarda (<=0.01%), erythema multiforme (<=0.01%), Stevens Johnson syndrome (<=0.01%), toxic epidermal necrolysis (<=0.01%).
Special Senses
Taste disorder (0.2%).
Cardiovascular
Syncope (0.3%), thrombophlebitis (0.2%), vasculitis (0.1%), angina (0.1%), arrhythmia (0.1%), myocardial infarction (0.1%).
Respiratory
Cough (0.6%), asthma (0.4%), eosinophilic pneumonia (<=0.01%), hypersensitivity pneumonitis (<=0.01%), interstitial pneumonitis (<=0.01%).
Renal/Genitourinary
Dysuria (0.7%), albuminuria (0.5%), hematuria (0.4%), impotence (0.2%), renal stones (0.2%), hyperuricemia (0.1%), azotemia (0.1%), interstitial nephritis (<=0.01%), nephrotic syndrome (<=0.01%), renal failure (<=0.01%), vaginal bleeding (<=0.01%).
Other
Edema (0.7%), weight gain (0.7%), weight loss (0.4%), fever (0.4%), chills (0.2%), hyperglycemia (0.2%), hypokalemia (0.1%).
Hematologic/Lymphatic
Anemia (0.5%), leucopenia (0.4%), thrombocytopenia (0.2%), granulocytopenia (0.1%), aplastic anemia (<0.01).
Hepatic
Liver function abnormalities (0.5%), elevated liver function tests (<=0.01%), jaundice (<=0.01%), hepatic failure (<=0.01%).
Allergic/Hypersensitivity
Angioneurotic edema (<0.01%), anaphylactoid reaction (<0.01%), anaphylaxis (<0.01%).
Drug-Drug Interactions
In vitro
studies have shown that, because of its affinity for protein, the active metabolite of nabumetone may displace other protein-bound drugs such as sulfonylureas, tolbutamide, chlorpropamide and warfarin, from their binding site. However, clinical pharmacology studies demonstrated no significant drug interaction between warfarin and nabumetone.
Numerous studies have shown that the concomitant use of NSAIDs and anticoagulants increase the risk of GI adverse events such as ulceration and bleeding. For these reasons, the concomitant administration of nabumetone and warfarin or other highly protein bound drugs should be undertaken with caution. In addition, because prostaglandins play an important role in hemostasis, and NSAIDs affect platelet function, concurrent therapy of nabumetone with warfarin requires close monitoring to be certain that no change in anticoagulant dosage is necessary. Digoxin levels should be monitored, and if necessary, a dosage adjustment made when administered concomitantly with nabumetone. NSAIDs have also been reported to increase steady-state plasma lithium concentrations. It is recommended that these concentrations be monitored when initiating, adjusting or discontinuing nabumetone treatment. Rare cases of fatal renal toxicity have occurred when methotrexate and NSAIDs are given concomitantly. Concomitant administration of an aluminum-containing antacid had no significant effect on the bioavailability of 6-MNA. Concomitant administration of paracetamol, ASA or cimetidine did not affect the bioavailability of the principal circulating metabolite in volunteer subjects. Numerous studies have shown that the concomitant use of NSAIDs and oral glucocorticoids increases the risk of GI side effects such as ulceration and bleeding. This is especially the case in older (>65 years of age) individuals. In controlled rheumatoid arthritis trials, nabumetone has been used in combination with gold, d- penicillamine, and corticosteroids. There was no evidence of untoward effects associated with their concurrent administration. No specific drug interaction studies have been conducted with nabumetone and antihypertensives, oral contraceptives, diuretics, cyclosporine, probenecid, aminoglycosides, cholestyramine, oral hypoglycemic agents or alcohol.
Recommended Dose and Dosage Adjustment
The starting and usual adult dose is 1000 mg daily taken as a single dose with or without food. The dosage may be increased to 1500 mg or 2000 mg per day given either as a single dose or in two divided doses. Since nabumetone has an average plasma half-life of 23 hours in healthy young subjects and 30 hours in elderly patients, plasma levels of 6-MNA will approximate steady-state within one week of dosing. For this reason, dosage adjustments during therapy should not be made more frequently than at one-week intervals, except in the case of side effects. In patients with severe renal or hepatic impairment, dosage level adjustments should be made on an individual basis. In moderate renal impairment dose reduction may be warranted (see WARNINGS AND PRECAUTIONS, and DRUG INTERACTIONS).
Overdoses with nabumetone have been rarely reported. There is no specific antidote and the active metabolite 6-MNA is not dialysable. If acute overdosage occurs, it is recommended that the stomach be emptied by vomiting or lavage and institution of general supportive measures as necessary. In addition, the use of activated charcoal, up to 60 g, may effectively reduce nabumetone absorption. Co-administration of nabumetone with activated charcoal orally in man has resulted in an 80% decrease in maximum plasma concentrations of the active metabolite. For management of a suspected drug overdose, contact your regional Poison Control Centre.
Mechanism of Action
Nabumetone is a non-acidic, NSAID with a naphthylalkanone structure which is virtually insoluble in water. It exhibits anti-inflammatory, analgesic and antipyretic properties in pharmacologic studies. As with the acidic NSAIDs, its mode of action is not known. However, the ability to inhibit prostaglandin synthesis may be involved in the anti-inflammatory effect. Nabumetone as the parent compound is a pro-drug which undergoes rapid hepatic biotransformation to its principal active metabolite, 6-methoxy-2-naphthylacetic acid (6-MNA), a potent inhibitor of prostaglandin biosynthesis. Nabumetone was compared to ASA 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 three or four weeks' therapy of nabumetone 1000 mg or 2000 mg daily when compared to either placebo-treated or non-treated subjects. In contrast, ASA 3600 mg daily produced an increase in fecal blood loss when compared to the nabumetone, placebo or non- treated subjects. In one week repeat dose studies in healthy volunteers, nabumetone 1000 mg daily had little effect on collagen-induced platelet aggregation and no effect on bleeding time.
Pharmacokinetics
Table 2 - Mean Pharmacokinetic Parameters Of Nabumetone Active Metabolite (6-MNA) at Steady-State Following Oral Administration of 1000 mg or 2000 mg Doses of Nabumetone
| Abbreviations (units) | Young Adults | Young Adults | Elderly |
| Mean +- SD 1000 mg n=31 | Mean +- SD 2000 mg n=12 | Mean +- SD 1000 mg n=27 | |
| t m ax (hours) * | 3.0 ( 1.0 to 12.0) | 2.5 (1.0 to 8.0) | 4.0 (1.0 to 10.0) |
| t 1/2 (hours) | 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 |
*tmax is reported as median (range) values.
After oral administration, approximately 80% of a radio-labelled dose of nabumetone is found in the urine, indicating that nabumetone is well absorbed from the gastrointestinal tract. Following oral administration, peak plasma levels of 6-MNA occur between 2.5 and 4 hours (range 1 to 12 hours). When administered with food or milk, there is more rapid absorption; however, the total amount of 6-MNA in the plasma is unchanged.
Preliminary in vivo and in vitro studies suggest that unlike other NSAIDs, there is no evidence of enterohepatic recirculation of the active metabolite. Steady-state is generally achieved between 3 and 6 days and the elimination half-life is variable from 23 (+-3.7) hours in young healthy patients to 30 (+-8.1) hours in the elderly. The active metabolite penetrates into the synovial fluids at measurable sustained levels in osteoarthritis and rheumatoid arthritis patients. There is wide inter-individual variation in plasma concentrations of 6-MNA. A correlation between plasma 6-MNA levels and efficacy has not been established. 6-MNA is more than 99% bound to plasma proteins. The free fraction is dependent on total concentration of 6-MNA and is proportional to dose over the range of 1000 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.
Nabumetone itself is not quantifiable in the plasma because, after absorption, it undergoes rapid biotransformation to the principal active metabolite, 6-MNA. Approximately 35% of a 1000 mg dose of nabumetone is converted to 6-MNA and 50% is converted into unidentified metabolites which are subsequently excreted in the urine.
After oral administration, approximately 80% of a radio-labelled dose of nabumetone is found in the urine.
Special Populations and Conditions
Steady-state plasma concentrations in elderly patients were generally higher than in young healthy subjects (See Table 2).
Data in patients with severe hepatic impairment are limited. Biotransformation of nabumetone to 6-MNA and the further metabolism of 6-MNA to inactive metabolites is dependent on hepatic function and could be reduced in patients with severe hepatic impairment (history of or biopsy- proven cirrhosis).
In studies of patients with renal insufficiency, the mean terminal half-life of 6-MNA was increased in patients with severe renal dysfunction (creatinine clearance <30 mL/min/1.73 m2 or <0.5 mL/sec/1.73 m2). In patients undergoing hemodialysis, steady state plasma concentrations of the active metabolite were similar to those observed in healthy subjects. Due to extensive protein binding, 6-MNA is not dialyzable.
APO-NABUMETONE (Nabumetone Tablets) should be stored at room temperature (15 - 30degC) in a dry place and dispensed in a light resistant container.
APO-NABUMETONE (Nabumetone Tablets) is available as 500 mg tablets. Each white, modified capsule-shaped, biconvex, film-coated tablet engraved "APO" on one side and "500" on the other, contains 500 mg nabumetone. Available in bottles of 60, 100, 250, 500 and 1000 tablets. In addition to the active ingredient, APO-NABUMETONE Tablets contain the following non- medicinal ingredients: croscarmellose sodium, hydroxypropyl cellulose, magnesium stearate, polyethylene glycol, sodium lauryl sulphate and titanium dioxide.