Nonsteroidal Anti-inflammatory Agent
Action And Clinical Pharmacology: Nabumetone is a nonacidic, nonsteroidal anti-inflammatory drug (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 1r-tagged red blood cells in healthy males showed no difference in fecal blood loss after 3 or 4 weeks’ therapy of nabumetone 1 000 or 2 000 mg daily when compared to either placebo-treated or nontreated subjects. In contrast, ASA 3 600 mg daily produced an increase in fecal blood loss when compared to the nabumetone, placebo- or nontreated subjects.
In 1 week repeat dose studies in healthy volunteers, nabumetone 1 000 mg daily had little effect on collagen-induced platelet aggregation and no effect on bleeding time.
Pharmacokinetics: After oral administration, approximately 80% of a radio-labeled dose of nabumetone is found in the urine, indicating that nabumetone is well absorbed from the gastrointestinal tract. 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 1 000 mg dose of nabumetone is converted to 6-MNA and 50% is converted into unidentified metabolites which are subsequently excreted in the urine. Following oral administration, peak plasma levels of 6-MNA occur between 2.5 and 4 hours (range 1 to 12 hours). 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 (Â±3.7) hours in young healthy patients to 30 (Â±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 1 000 to 2 000 mg. It is 0.2% to 0.3% at concentrations typically achieved following administration of nabumetone 1 000 mg and is approximately 0.6% to 0.8% of the total concentrations at steady-state following daily administration of 2 000 mg.
Concomitant administration of an aluminum-containing antacid had no significant effect on the bioavailability of the active metabolite of nabumetone. When administered with food or milk, there is more rapid absorption; however, the total amount of 6-MNA in the plasma is unchanged.
Geriatrics: Steady-state plasma concentrations in elderly patients were generally higher than in young healthy subjects.
Renal Insufficiency: 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
Hepatic Impairment: 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).
Indications And Clinical Uses: For acute and chronic relief of the signs and symptoms of rheumatoid arthritis and osteoarthritis.
Contra-Indications: In patients who have previously exhibited hypersensitivity to nabumetone.
Nabumetone should not be given to patients in whom ASA or other NSAIDs induce asthma, urticaria or other allergic type reactions. Fatal anaphylactoid reactions have occurred in such individuals.
Manufacturers’ Warnings In Clinical States: Risk of Gastrointestinal Ulceration, Bleeding and Perforation with NSAID Therapy: Peptic ulceration, perforation and gastrointestinal bleeding, sometimes severe and occasionally fatal have been reported during therapy with NSAIDs including nabumetone.
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. In these cases the physician must weigh the benefits of treatment against the possible hazards.
Patients taking any NSAID including this drug should be instructed to contact a physician immediately if they experience symptoms or signs suggestive of peptic ulceration or gastrointestinal bleeding. These reactions can occur without warning symptoms or signs and at any time during the treatment.
Elderly, frail and debilitated patients appear to be at higher risk from a variety of adverse reactions from NSAIDs. However, data from clinical studies with nabumetone 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. See Precautions for further advice.
Pregnancy and Lactation: As the safety and efficacy of nabumetone in human pregnancy and lactation have not been established, its use is therefore 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.
Children: Nabumetone is not recommended for use in children because the safety and efficacy in children have not been established.
Precautions: Gastrointestinal: If peptic ulceration is suspected or confirmed, or if gastrointestinal bleeding or perforation occurs, nabumetone should be discontinued, and appropriate treatment instituted and the patient closely monitored.
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.
Hepatic Impairment: As with other NSAIDs, borderline elevations of one or more liver tests may occur. These abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy. 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 other 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 this drug is to be used in the presence of impaired liver function, it must be done under strict observation.
Renal Impairment: As with other NSAIDs, long-term administration of nabumetone 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.
A second form of renal toxicity has been seen in patients with prerenal 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 great caution in patients with impaired renal function. Although studies have shown that no adjustment of dosage is generally necessary in patients with renal insufficiency, as with other NSAIDs, patients with severely impaired renal function should be monitored more closely than patients with normal renal function.
During long-term therapy, kidney function should be monitored periodically.
Geriatrics: 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 1 677 patients were Â³65 years of age) and UK postmarketing studies with nabumetone (where 43% of 10 800 patients were Â³65 years of age) indicate that there were no differences in efficacy or safety between older and younger patients.
Fluid and Electrolyte Balance: 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 b-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.
Hematology: Drugs inhibiting prostaglandin biosynthesis do interfere with platelet function to some degree; therefore, patients who may be adversely affected by such an action should be carefully observed when nabumetone is administered. Blood dyscrasias associated with the use of NSAIDs are rare, but could have severe consequences.
Hypersensitivity: 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.
Infection: In common with other anti-inflammatory drugs, nabumetone may mask the usual signs of infection.
Ophthalmology: 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 examination should be carried out at periodic intervals in any patients receiving this drug for an extended period of time.
Occupational Hazards: Dizziness or other disturbances of the CNS may occur following therapy with nabumetone. Patients experiencing these symptoms should be cautioned against driving or operating machinery.
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. Although clinical pharmacology studies demonstrated no significant drug interaction between warfarin and nabumetone, concomitant administration of nabumetone and warfarin or other highly protein-bound drugs should be undertaken with caution.
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. When administered with food or milk, there is more rapid absorption; however, the total amount of 6-MNA in the plasma is unchanged.
Concomitant administration of acetaminophen, ASA or cimetidine did not affect the bioavailability of the principal circulating metabolite in volunteer subjects.
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.
Adverse Reactions: 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 on occasion particularly in the elderly.
Adverse reaction information was derived from blinded-controlled and open-labeled 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 postmarketing surveillance studies and nabumetone has been prescribed extensively in those countries where the drug has received registration clearance.
In large scale postmarketing 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 to 2 g doses, and was similar in patients aged
In the description below, information on adverse experiences observed in U.S. clinical studies is presented. 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. Over 300 patients have been treated for 5 years or longer.
The most frequently reported adverse reactions were related to the gastrointestinal tract. They were diarrhea, dyspepsia and abdominal pain. Of 1 677 patients treated with nabumetone in controlled clinical trials (1 140 followed for 1 year and 927 for 2 years), the cumulative incidence of peptic ulcers was 0.3% at 3 to 6 months, 0.5% at 1 year and 0.8% at 2 years.
The following is a listing of adverse events reported in long-term clinical trial follow-up involving treatment for up to 8 years. Adverse events listed at an estimated incidence of Â£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.
Adverse Events: Gastrointestinal: diarrhea (14%), dyspepsia (13%), abdominal pain (12%), nausea (9%), flatulence (6%), constipation (4%), positive stool guaiac (2%), dry mouth (2%), gastritis (1%), vomiting (1%), melena 1%), eructation 0.7%), gastoenteritis (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 (Â£0.01%), gallstones (Â£0.01%).
CNS: headache (8%), dizziness (6%), insomnia (3%), fatigue (2%), somnolence (2%), increased sweating (1%), nervousness (1%), 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
Dermatologic: rash (7%), pruritus (4%), alopecia (0.9%), urticaria (0.7%), acne (0.4%), bullous eruptions (0.2%), photosensitivity (0.2%), pseudoporphyria cutanea tarda (Â£0.01%), erythema multiforme (Â£0.01%), Stevens-Johnson syndrome (Â£0.01%), toxic epidermal necrolysis (Â£0.01%).
Special Senses: tinnitus (4%), abnormal vision (2%), taste disorder (0.2%).
Cardiovascular: hypertension (1.7%), palpitations (1%), syncope (0.3%), thrombophlebitis (0.2%), vasculitis (0.1%), angina (0.1%), arrhythmia (0.1%), myocardial infarction (0.1%).
Respiratory: dyspnea (1%), cough (0.6%), asthma (0.4%), eosinophilic pneumonia (Â£0.01%), hypersensitivity pneumonitis (Â£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 (Â£0.01%), vaginal bleeding (Â£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%), leukopenia (0.4%), thrombocytopenia (0.2%), granulocytopenia (0.1%), aplastic anemia (
Hepatic: liver function abnormalities (0.5%).
Allergic/Hypersensitivity: angioneurotic edema
Symptoms And Treatment Of Overdose: Symptoms and Treatment: Nabumetone overdose has been rarely reported. 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. Coadministration of nabumetone with activated charcoal orally in man has resulted in an 80% decrease in maximum plasma concentrations of the active metabolite. tag_DosageDosage
Dosage And Administration: Osteoarthritis and Rheumatoid Arthritis: The starting and usual adult dose is 1 000 mg daily taken as a single dose with or without food. The dosage may be increased to 1 500 mg or 2 000 mg/day given either as a single dose or in 2 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 1 week of dosing. For this reason, dosage adjustments during therapy should not be made more frequently than at 1 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.
Availability And Storage: 500 mg: Each white, pillow-shaped, film-coated tablet, with RELAFEN embossed on one side and 500 embossed on the other side, contains: nabumetone 500 mg. Nonmedicinal ingredients: hydroxypropyl methylcellulose, microcrystalline cellulose, sodium starch glycolate and sodium lauryl sulfate. Film coating: coloring and titanium dioxide. Polyethylene bottles of 60.
750 mg: Each beige, pillow-shaped, film-coated tablet, with RELAFEN embossed on one side and 750 embossed on the other side, contains: nabumetone 750 mg. Nonmedicinal ingredients: hydroxypropyl methylcellulose, microcrystalline cellulose, sodium starch glycolate and sodium lauryl sulfate. Film coating: coloring and titanium dioxide. Polyethylene bottles of 100.
Store between 15 and 30°C in a dry place and dispense in a light-resistant container.
RELAFEN SmithKline Beecham Nabumetone Nonsteroidal Anti-inflammatory Agent
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