Relafen (nabumetone) is a naphthylalkanone desig- nated chemically as 4-(6-methoxy-2-naphthalenyl)-2- butanone. It has the following structure:
CH3O nabumetone Nabumetone is a white to off-white crystalline sub- stance with a molecular weight of 228.3. It is non-
CONCENTRATION
(mcg/mL)
2000 mg/day
TIME (hours)
Osteoarthritis: The use of Relafen in relieving the signs and symptoms of osteoarthritis was assessed in double-blind controlled trials in which 1,047 patients were treated for 6 weeks to 6 months. In these trials, Relafen in a dose of 1000 mg/day administered at night was comparable to naproxen 500 mg/day and to aspirin 3600 mg/day. Rheumatoid Arthritis: The use of Relafen in reliev- ing the signs and symptoms of rheumatoid arthritis was assessed in double-blind, randomized, controlled trials in which 770 patients were treated for 3 weeks to 6 months. Relafen, in a dose of 1000 mg/day ad- ministered at night was comparable to naproxen 500 acidic 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 oval-shaped, film-coated tablet contains 500 mg or 750 mg of nabumetone. Inactive ingredients consist of hydroxy- propyl methylcellulose, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium lauryl sul-
The 750 mg tablets also contain iron oxides.
Relafen
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. 6MNA undergoes biotransformation in the liver, pro- ducing 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 sug- gest that unlike other NSAIDs, there is no evidence of enterohepatic recirculation of the active metabolite. Approximately 75% of a radiolabelled dose was re- covered in urine in 48 hours. Approximately 80% was feces. In the first 48 hours, metabolites consisted of: -nabumetone, unchanged not detectable -6-methoxy-2-naphthylacetic acid <1% (6MNA), unchanged -6MNA, conjugated 11% -6-hydroxy-2-naphthylacetic acid 5% (6HNA), unchanged -6HNA, conjugated 7% -4-(6-hydroxy-2-naphthyl)-butan-2-ol, 9% conjugated -O-desmethyl-nabumetone, conjugated 7% -unidentified minor metabolites 34% Total % Dose: 73% Following oral administration of dosages of 1000 mg to 2000 mg to steady state, the mean plasma clear- ance of 6MNA is 20 to 30 mL/min. and the elimination half-life is approximately 24 hours. mg/day and to aspirin 3600 mg/day. In controlled clinical trials of rheumatoid arthritis pa- tients, Relafen has been used in combination with gold, d-penicillamine and corticosteroids.
There is considerable interpatient variation in response to Relafen. Therapy is usually initiated at a Relafen dose of 1000 mg daily, then adjusted, if needed, In clinical trials with osteoarthritis and rheumatoid arthritis patients, most patients responded to Relafen in doses of 1000 mg/day administered nightly; total daily dosages up to 2000 mg were used. In open- labelled studies, 1,490 patients were permitted dos- age increases and were followed for approximately 1 year (mode). Twenty percent of patients (n=294) were withdrawn for lack of effectiveness during the first year of these open-labelled studies. The follow- ing table provides patient-exposure to doses used in the U.S. clinical trials:
Table 2. Clinical double-blind and open-labelled trials of Relafen (nabumetone) in osteoarthritis and rheumatoid arthritis
Number of Duration of
Patients Treatment (yrs.)
| CH 3 O | Elderly Patients: Steady-state plasma concentra- | 500 mg | 17 | 6 | 0.4/- | 0.2/- |
| tions in elderly patients were generally higher than in | 1000 mg | 917 | 701 | 1.2/1 | 1.4/1 | |
| 6-methoxy-2-naphthylacetic acid (6MNA) | young healthy subjects. (See Table 1 for summary of | 1500 mg | 645 | 224 | 2.3/1 | 1.7/1 |
| acidic and has an n-octanol:phosphate buffer | pharmacokinetic parameters.) | 2000 mg | 15 | 100 | 0.6/1 | 1.3/1 |
Relafen
Dose OA RA OA RA
It is partition coefficient of 0.5 at pH 7.4.
After oral administration, approximately 80% of a radiolabelled 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 to 6MNA and 50% is converted into unidentified metabolites which are subsequently excreted in the urine. Following oral administration of Relafen, 6MNA exhibits pharmaco- kinetic 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 con- centrations typically achieved following administra- tion of Relafen 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 absorp- tion and subsequent appearance of 6MNA in the plasma but does not affect the extent of conversion of nabumetone into 6MNA. Peak plasma concentra- tions of 6MNA are increased by approximately one third. Coadministration with an aluminum-containing ant- acid had no significant effect on the bioavailability of 6MNA. Renal Insufficiency: In studies of patients with renal insufficiency, the mean terminal half-life of 6MNA was increased in patients with severe renal dysfunc- tion (creatinine clearance <30 mL/min./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, 6MNA is not dialyzable.
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).
Gastrointestinal: Relafen (nabumetone) was com- pared to aspirin 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 3 or 4 weeks' administration of Relafen 1000 mg or 2000 mg 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 com- pared to the Relafen-treated, placebo-treated or non- treated subjects. 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 clini- cal 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 pa- tients who had baseline and post-treatment endos- copy. In 5 clinical trials that compared a total of 194 patients on Relafen 1000 mg daily or naproxen 250 As with other NSAIDs, the lowest dose should be sought for each patient. Patients weighing under 50 kg may be less likely to require dosages beyond 1000 mg. Therefore, after observing the response to initial therapy, the dose should be adjusted to meet individual patients' requirements.
Relafen
is indicated for acute and chronic treatment of signs and symptoms of osteoarthritis and rheumatoid arthritis.
Relafen
is contraindicated in patients who have pre- viously exhibited hypersensitivity to it.
Relafen is contraindicated in patients in whom Relafen, aspirin or other NSAIDs induce asthma, urticaria or other allergic-type reactions. Fatal asthmatic reactions have been reported in such patients receiving NSAIDs.
Serious gastrointestinal toxic- ity such as bleeding, ulceration and perforation can occur at any time, with or without warning symptoms, in patients treated chronically with NSAID therapy. Al- though minor upper gastrointestinal problems, such as dyspepsia, are common, usually developing early in therapy, physicians should remain alert for ulcera- tion and bleeding in patients treated chronically with NSAIDs even in the absence of previous G.I. tract symptoms.
In controlled clinical trials involving 1,677 patients treated with Relafen (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 symptoms
continued
of serious G.I. toxicity and what steps to take if they occur. In patients with active peptic ulcer, physicians must weigh the benefits of Relafen (nabumetone) therapy against possible hazards, institute an appro- priate ulcer treatment regimen and monitor the pa- tients' progress carefully. Studies to date have not identified any subset of patients not at risk of developing peptic ulceration and bleeding. Except for a prior history of serious G.I. events and other risk factors known to be associated with peptic ulcer disease, such as alcoholism, smok- ing, etc., no risk factors (e.g., age, sex) have been associated with increased risk. Elderly or debilitated patients seem to tolerate ulceration or bleeding less well than other individuals and most spontaneous reports of fatal G.I. events are in this population. High doses of any NSAID probably carry a greater risk of these reactions, although controlled clinical trials showing this do not exist in most cases. In consider- ing the use of relatively large doses (within the rec- ommended dosage range), sufficient benefit should be anticipated to offset the potential increased risk of G.I. toxicity.
Renal Effects:
As a class, NSAIDs have been associ- ated with renal papillary necrosis and other abnormal renal pathology during long-term administration to animals.
A second form of renal toxicity often associated with NSAIDs is seen in patients with conditions leading to a reduction in renal blood flow or blood volume, where renal prostaglandins have a supportive role in the maintenance of renal perfusion. In these patients, administration of an NSAID results in a dose-depen- dent decrease in prostaglandin synthesis and, sec- ondarily, 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. Because nabumetone undergoes extensive hepatic metabolism, no adjustment of Relafen dosage is gen- erally necessary in patients with 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, Renal Insufficiency). In patients with severe renal impairment (creatinine clearance
<=
30 mL/min. ), laboratory tests should be performed at baseline and within weeks of starting therapy. Further tests should be carried out as necessary; if the impair- ment worsens, discontinuation of therapy may be warranted. The oxidized and conjugated metabolites of 6MNA are eliminated primarily by the kidneys. The extent to which these largely inactive metabo- lites may accumulate in patients with renal failure has not been studied. As with other drugs whose metabolites are excreted by the kidneys, the possi- bility that adverse reactions (not listed in ADVERSE REACTIONS) may be attributable to these metabo- lites should be considered.
Hepatic Function: As with other NSAIDs, borderline elevations of one or more liver function 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 indi- cator 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 Relafen (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 a more severe hepatic reaction while on Relafen therapy. Severe hepatic reactions, includ- ing jaundice and 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. ), Relafen should be discontinued. Because nabumetone's biotrans- formation to 6MNA is dependent upon hepatic func- tion, the biotransformation could be decreased in patients with severe hepatic dysfunction. Therefore, Relafen should be used with caution in patients with severe hepatic impairment (see Pharmacokinetics, Hepatic Impairment). Fluid Retention and Edema: Fluid retention and edema have been observed in some patients taking Relafen. Therefore, as with other NSAIDs, Relafen should be used cautiously in patients with a history of congestive heart failure, hypertension or other conditions predisposing to fluid retention. Photosensitivity: Based on U.V. light photosensitiv- ity testing, Relafen may be associated with more reactions to sun exposure than might be expected based on skin tanning types.
like other drugs of its class, is not free of side effects. The side effects of these drugs can cause discomfort and, rarely, there are more serious side effects, such as gastrointesti- nal bleeding, which may result in hospitalization and even fatal outcome.
NSAIDs are often essential agents in the manage- ment of arthritis, but they also may be commonly employed for conditions which are less serious. Phy- sicians may wish to discuss with their patients the potential risks (see WARNINGS, PRECAUTIONS and ADVERSE REACTIONS) and likely benefits of NSAID treatment, particularly when the drugs are used for less serious conditions where treatment without NSAIDs may represent an acceptable alternative to both the patient and the physician.
Because severe G.I. tract ulcera- tion and bleeding can occur without warning symp- toms, physicians should follow chronically treated patients for signs and symptoms of ulceration and bleeding, and should inform them of the importance of this follow-up (see WARNINGS, Risk of G.I. Ulcer- ation, Bleeding and Perforation with NSAID Therapy).
Drug Interactions: In vitro studies have shown that, because of its affinity for protein, 6MNA may dis- place other protein-bound drugs from their binding site. Caution should be exercised when administer- ing Relafen with warfarin since interactions have been seen with other NSAIDs. Concomitant administration of an aluminum-contain- ing antacid had no significant effect on the bioavail- ability of 6MNA. When administered with food or milk, there is more rapid absorption; however, the total amount of 6MNA in the plasma is unchanged (see Pharmacokinetics). Carcinogenesis, Mutagenesis: In two-year studies conducted in mice and rats, nabumetone had no sta- tistically significant tumorigenic effect. Nabumetone did not show mutagenic potential in the Ames test and mouse micronucleus test in vivo. However, na- bumetone- and 6MNA-treated lymphocytes in culture showed chromosomal aberrations at 80 mcg/mL and higher concentrations (equal to the average human exposure to Relafen at the maximum recommended dose). Impairment of Fertility: Nabumetone did not impair fertility of male or female rats treated orally at doses of 320 mg/kg/day (1888 mg/m2) before mating. Pregnancy: Teratogenic Effects. Pregnancy Cate- gory C. Nabumetone did not cause any teratogenic effect in rats given up to 400 mg/kg (2360 mg/m2) and in rabbits up to 300 mg/kg (3540 mg/m2) orally. However, increased post-implantation loss was ob- served in rats at 100 mg/kg (590 mg/m2) orally and at higher doses (equal to the average human exposure to 6MNA at the maximum recommended human dose). There are no adequate, well-controlled studies in pregnant women. This drug should be used during pregnancy only if clearly needed. Because of the known effect of prostaglandin-syn- thesis-inhibiting drugs on the human fetal cardiovas- cular system (closure of ductus arteriosus), use of Relafen (nabumetone) during the third trimester of pregnancy is not recommended. Labor and Delivery: The effects of Relafen on labor and delivery in women are not known. As with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia and delayed parturi- tion occurred in rats treated throughout pregnancy.
is not recommended for use in nursing mothers because of the possible ad- verse effects of prostaglandin-synthesis-inhibiting drugs on neonates. It is not known whether nabume- tone or its metabolites are excreted in human milk; however, 6MNA is excreted in the milk of lactating rats.
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use: Of the 1,677 patients in U.S. clinical studies who were treated with Relafen, 411 patients (24%) were 65 years of age or older; 22 patients (1%) were 75 years of age or older. No overall differences in efficacy or safety were observed between these older patients and younger ones. Similar results were observed in a 1-year, non-U.S. postmarketing surveil- lance study of 10,800 Relafen patients, of whom 4,577 patients (42%) were 65 years of age or older.
Adverse reaction information was derived from blind- ed-controlled and open-labelled clinical trials and from worldwide 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 Relafen 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 diar- rhea, 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, gastrointes- tinal bleeding, increased appetite, liver function abnor- malities, melena, hepatic failure.
Central Nervous System:
Asthenia, agitation, anxi- ety, confusion, depression, malaise, paresthesia, tremor, vertigo.
Dermatologic: toxic epi- dermal necrolysis, erythema multiforme, Stevens- Johnson Syndrome.
Bullous eruptions, photosensitivity, urticaria, pseudoporphyria cutanea tarda,
Cardiovascular:
Vasculitis.
Metabolic:
Weight gain.
Respiratory: eosinophilic pneumonia, hypersensitivity pneumonitis, idiopathic interstitial pneumonitis.
Dyspnea,
Genitourinary: hyperuri- cemia, interstitial nephritis, nephrotic syndrome, vaginal bleeding, renal failure.
Albuminuria, azotemia,
Special Senses:
Abnormal vision.
Hematologic/Lymphatic: Thrombocytopenia
.
Hypersensitivity: Anaphylactoid reaction, anaphy- laxis,
angioneurotic edema.
+Adverse reactions reported only in worldwide postmarketing expe- rience or in the literature, not seen in clinical trials, are considered rarer and are italicized.
Incidence 1%--Causal Relationship Unknown
<
++
Gastrointestinal:
Bilirubinuria, duodenitis, eructa- tion, gallstones, gingivitis, glossitis, pancreatitis, rec- tal bleeding.
Central Nervous System:
Nightmares.
Dermatologic:
Acne, alopecia.
Cardiovascular:
Angina, arrhythmia, hypertension, myocardial infarction, palpitations, syncope, throm- bophlebitis.
Respiratory:
Asthma, cough.
Genitourinary:
Dysuria, hematuria, impotence, renal stones.
Special Senses:
Taste disorder.
Body as a Whole:
Fever, chills.
Hematologic/Lymphatic:
Anemia, leukopenia, gran- ulocytopenia.
Metabolic/Nutritional:
Hyperglycemia, hypokalemia, weight loss.
++Adverse reactions reported only in worldwide postmarketing expe- rience or in the literature, not seen in clinical trials, are considered rarer and are italicized.
Symptoms following acute NSAIDs overdoses are usually limited to lethargy, drowsiness, nausea, vom- iting, and epigastric pain, which are generally revers- ible with supportive care. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respira- tory depression and coma may occur, but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur fol- lowing 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 indicat- ed 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 Relafen reported with no long-term sequelae follow- ing standard emergency treatment (i.e., activated charcoal, gastric lavage, IV H2-blockers, etc. ).
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. Relafen (nabumetone) can be given in either a single or twice-daily dose. Dosages over 2000 mg per day have not been studied. The lowest effective dose should be used for chronic treatment.
Oval-shaped, film-coated: 500 mg-white, imprinted with the product name RELAFEN and 500, in bottles of 100, and in Single Unit Packages of 100 (intended for institutional use only). 750 mg-beige, imprinted with the product name RELAFEN and 750, in bottles of 100, and in Single Unit Packages of 100 (intended for institutional use only).
Store at 25degC (77degF); excursions permitted to 15-30degC (59-86degF) in well-closed container; dispense in light- resistant container. 500 mg 100's: NDC 0029-4851-20 500 mg SUP 100's: NDC 0029-4851-21 750 mg 100's: NDC 0029-4852-20 750 mg SUP 100's: NDC 0029-4852-21
DATE OF ISSUANCE OCT 2000
(c) SmithKline Beecham, 2000
Philadelphia, PA 19101
RL:L10 Printed in U.S.A.