Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/1882
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RELAFEN (Tablet, Film Coated)
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Carefully consider the potential benefits and risks of RELAFEN
and other treatment options before deciding to use RELAFEN. 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 RELAFEN, the dose and frequency should be
adjusted to suit an individual patient's needs.<br/>Osteoarthritis and Rheumatoid Arthritis: The recommended starting
dose is 1,000 mg taken as a single dose with or without food. Some patients
may obtain more symptomatic relief from 1,500 mg to 2,000 mg per
day. RELAFEN can be given in either a single or twice-daily dose. Dosages
greater than 2,000 mg per day have not been studied. The lowest effective
dose should be used for chronic treatment (see WARNINGS, Renal Effects). Patients
weighing under 50 kg may be less likely to require dosages beyond 1,000 mg;
therefore, after observing the response to initial therapy, the dose should
be adjusted to meet individual patients' requirements.
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RELAFEN (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 with a molecular weight of 228.3. 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.<br/>Tablets for Oral Administration: Each oval-shaped, film-coated
tablet contains 500 mg or 750 mg of nabumetone. Inactive ingredients
consist of hypromellose, microcrystalline cellulose, polyethylene glycol,
polysorbate 80, sodium lauryl sulfate, sodium starch glycolate, and titanium
dioxide. The 750-mg tablets also contain iron oxides.
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RELAFEN is a non-steroidal
anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic,
and antipyretic properties in pharmacologic studies. As with other non-steroidal
anti-inflammatory agents, its mode of action is not known; however, the ability
to inhibit prostaglandin synthesis may be involved in the anti-inflammatory
effect. The parent compound is a prodrug, which undergoes
hepatic biotransformation to the active component, 6-methoxy-2-naphthylacetic
acid (6MNA), that is a potent inhibitor of prostaglandin synthesis. 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 1,000-mg oral dose of nabumetone is converted to 6MNA
and 50% is converted into unidentified metabolites which are subsequently
excreted in the urine. Following oral administration of RELAFEN, 6MNA exhibits
pharmacokinetic characteristics that generally follow a one-compartment model
with first order input and first order elimination. 6MNA
is more than 99% bound to plasma proteins. The free fraction is dependent
on total concentration of 6MNA and is proportional to dose over the range
of 1,000 mg to 2,000 mg. It is 0.2% to 0.3% at concentrations typically
achieved following administration of 1,000 mg of RELAFEN and is approximately
0.6% to 0.8% of the total concentrations at steady state following daily administration
of 2,000 mg. Steady-state plasma concentrations
of 6MNA are slightly lower than predicted from single-dose data. This may
result from the higher fraction of unbound 6MNA which undergoes greater hepatic
clearance. Coadministration of food increases the rate
of absorption and subsequent appearance of 6MNA in the plasma but does not
affect the extent of conversion of nabumetone into 6MNA. Peak plasma concentrations
of 6MNA are increased by approximately one third. Coadministration
with an aluminum-containing antacid had no significant effect on the bioavailability
of 6MNA. The simulated curves in the graph below illustrate the
range of active metabolite plasma concentrations that would be expected from
95% of patients following 1,000-mg to 2,000-mg doses to steady state. The
cross-hatched area represents the expected overlap in plasma concentrations
due to intersubject variation following oral administration of 1,000 mg
to 2,000 mg of RELAFEN. 6MNA
undergoes biotransformation in the liver, producing inactive metabolites that
are eliminated as both free metabolites and conjugates. None of the known
metabolites of 6MNA has been detected in plasma. Preliminary in vivo
and in vitro studies suggest that unlike other NSAIDs, there is no evidence
of enterohepatic recirculation of the active metabolite. Approximately 75%
of a radiolabeled dose was recovered in urine in 48 hours. Approximately
80% was recovered in 168 hours. A further 9% appeared in the feces. In
the first 48 hours, metabolites consisted of: Following oral administration of dosages of 1,000 mg
to 2,000 mg to steady state, the mean plasma clearance of 6MNA is 20
to 30 mL/min and the elimination half-life is approximately 24 hours.<br/>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).<br/>Renal Insufficiency: In moderate renal insufficiency patients (creatinine clearance
30 to 49 mL/min), the terminal half-life of 6MNA was increased by approximately
50% (39.2��7.8 hrs, N=12) compared to the normal subjects (26.9��3.3 hrs, N=13), and there was a 50% increase in the plasma levels of unbound
6MNA. Additionally, the renal excretion of 6MNA in
the moderate renal impaired patients decreased on average by 33% compared
to that in the normal patients. A similar increase in the mean terminal half-life
of 6MNA was seen in a small study of patients with severe renal dysfunction
(creatinine clearance<30 mL/min). In patients undergoing hemodialysis,
steady-state plasma concentrations of the active metabolite 6MNA were similar
to those observed in healthy subjects. Due to extensive protein binding, 6MNA
is not dialyzable Dosage adjustment of RELAFEN generally
is not necessary in patients with mild renal insufficiency (���50 mL/min).
Caution should be used in prescribing RELAFEN to patients with moderate or
severe renal insufficiency. The maximum starting doses of RELAFEN in patients
with moderate or severe renal insufficiency should not exceed 750 mg
or 500 mg, respectively once daily. Following careful monitoring of renal
function in patients with moderate or severe renal insufficiency, daily doses
may be increased to a maximum of 1,500 mg and 1,000 mg, respectively
(see WARNINGS: Renal Effects).<br/>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).<br/>Special Studies:<br/>Gastrointestinal: RELAFEN 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 1,000 mg or 2,000 mg of RELAFEN daily when compared to either
placebo-treated or nontreated subjects. In contrast, aspirin 3,600 mg
daily produced an increase in fecal blood loss when compared to subjects who
received RELAFEN, placebo, or no treatment. The clinical relevance of the
data is unknown. The following endoscopy trials entered
patients who had been previously treated with NSAIDs. These patients had varying
baseline scores and different courses of treatment. The trials were not designed
to correlate symptoms and endoscopy scores. The clinical relevance of these
endoscopy trials, i.e., either G.I. symptoms or serious G.I. events, is not
known. Ten endoscopy studies were conducted in 488 patients
who had baseline and post-treatment endoscopy. In 5 clinical trials that compared
a total of 194 patients on 1,000 mg of RELAFEN daily or naproxen 250 mg
or 500 mg twice daily for 3 to 12 weeks, treatment with RELAFEN
resulted in fewer patients with endoscopically detected lesions (>3 mm).
In 2 trials a total of 101 patients administered 1,000 mg or
2,000 mg of RELAFEN daily or piroxicam 10 mg to 20 mg for 7
to 10 days, there were fewer patients treated with RELAFEN with endoscopically
detected lesions. In 3 trials of a total of 47 patients on 1,000 mg
of RELAFEN 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 1,000 mg of RELAFEN daily to ibuprofen 2,400 mg/day and ibuprofen
2,400mg/day plus misoprostol 800 mcg/day. The results showed that
patients treated with RELAFEN 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.<br/>Other: In 1-week, repeat-dose studies in healthy volunteers, 1,000 mg
of RELAFEN 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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RELAFEN is contraindicated
in patients with known hypersensitivity to nabumetone or its excipients. RELAFEN
should not be given to patients who have experienced asthma, urticaria, or
allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely
fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients
(see WARNINGS, Anaphylactoid Reactions, and PRECAUTIONS, General, Preexisting Asthma). RELAFEN
is contraindicated for the treatment of peri-operative pain in the setting
of coronary artery bypass graft (CABG) surgery (see WARNINGS).
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Tablets: Oval-shaped, film-coated: 500 mg���white, imprinted
with the product name RELAFEN and 500, in bottles of 100. 750 mg���beige,
imprinted with the product name RELAFEN and 750, in bottles of 100. Store
at 25��C (77��F); excursions permitted to 15-30��C (59-86��F)
in well-closed container; dispense in light-resistant container. 500 mg
100's: NDC 0029-4851-20 750 mg 100's:
NDC 0029-4852-20<br/>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)? NSAID
medicines may increase the chance of a heart attack or stroke that can lead
to death. This chance increases: 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 (NSAID)? 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. MG-RL:1 GlaxoSmithKline Research
Triangle Park, NC 27709 ��2006, GlaxoSmithKline.
All rights reserved. February 2006 RL:L16
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Cardiovascular Risk:<br/>Gastrointestinal Risk:
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General: RELAFEN cannot be expected
to substitute for corticosteroids or to treat corticosteroid insufficiency.
Abrupt discontinuation of corticosteroids may lead to disease exacerbation.
Patients on prolonged corticosteroid therapy should have their therapy tapered
slowly if a decision is made to discontinue corticosteroids. The
pharmacological activity of RELAFEN in reducing fever and inflammation may
diminish the utility of these diagnostic signs in detecting complications
of presumed noninfectious, painful conditions.<br/>Hepatic Effects: Borderline elevations of 1 or more liver function tests
may occur in up to 15% of patients taking NSAIDs including RELAFEN. These
laboratory abnormalities may progress, may remain unchanged, or may be transient
with continuing therapy. Notable elevations of ALT or AST (approximately 3
or more times the upper limit of normal) have been reported in approximately
1% of patients in clinical trials with NSAIDs. In addition, rare cases of
severe hepatic reactions, including jaundice and fatal fulminant hepatitis,
liver necrosis and hepatic failure,some of them with fatal outcomes have
been reported. 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 therapy with
RELAFEN. If clinical signs and symptoms consistent with liver disease develop,
or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), RELAFEN
should be discontinued.<br/>Hematological Effects: Anemia is sometimes seen
in patients receiving NSAIDS, including RELAFEN. This may be due to fluid
retention, occult or gross GI blood loss, or an incompletely described effect
upon erythropoiesis. Patients on long-term treatment with NSAIDs, including
RELAFEN, should have their hemoglobin or hematocrit checked if they exhibit
any signs or symptoms of anemia. NSAIDs inhibit platelet
aggregation and have been shown to prolong bleeding time in some patients.
Unlike aspirin, their effect on platelet function is quantitatively less,
of shorter duration, and reversible. Patients receiving RELAFEN who may be
adversely affected by alterations in platelet function, such as those with
coagulation disorders or patients receiving anticoagulants, should be carefully
monitored (see CLINICAL PHARMACOLOGY, Special Studies, Other ).<br/>Preexisting Asthma: Patients with asthma
may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive
asthma has been associated with severe bronchospasm which can be fatal. Since
cross reactivity, including bronchospasm, between aspirin and other non-steroidal
anti-inflammatory drugs has been reported in such aspirin-sensitive patients,
RELAFEN should not be administered to patients with this form of aspirin sensitivity
and should be used with caution in patients with preexisting asthma.<br/>Photosensitivity: Based on ultraviolet (U.V.) light photosensitivity testing,
RELAFEN may be associated with more reactions to sun exposure than might be
expected based on skin tanning types.<br/>Information for Patients: Patients should be informed of
the following information before initiating therapy with an NSAID and periodically
during the course of ongoing therapy. Patients should also be encouraged to
read the NSAID Medication Guide that accompanies each prescription dispensed.<br/>Laboratory Tests: Because serious G.I. tract ulceration and bleeding can occur
without warning symptoms, physicians should monitor for signs and symptoms
of GI bleeding. Patients on long-term treatment with NSAIDs, should have their
CBC and a chemistry profile checked periodically. If clinical signs and symptoms
consistent with liver or renal disease develop, systemic manifestations occur
(e.g., eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen,
RELAFEN should be discontinued.<br/>Drug Interactions:<br/>ACE-inhibitors: Reports suggest that NSAIDs may diminish the antihypertensive
effect of ACE-inhibitors. This interaction should be given consideration in
patients taking NSAIDs concomitantly with ACE-inhibitors.<br/>Aspirin: When RELAFEN
is administered with aspirin, its protein binding is reduced, although the
clearance of free RELAFEN is not altered. The clinical significance of this
interaction is not known; however, as with other NSAIDs, concomitant administration
of nabumetone and aspirin is not generally recommended because of the potential
of increased adverse effects.<br/>Diuretics: Clinical studies,
as well as post marketing observations, have shown that RELAFEN can reduce
the natriuretic effect of furosemide and thiazides in some patients. This
response has been attributed to inhibition of renal prostaglandin synthesis.
During concomitant therapy with NSAIDs, the patient should be observed closely
for signs of renal failure (see PRECAUTIONS, Renal Effects), as well as to
assure diuretic efficacy.<br/>Lithium: NSAIDs have produced
an elevation of plasma lithium levels and a reduction in renal lithium clearance.
The mean minimum lithium concentration increased 15% and the renal clearance
was decreased by approximately 20%. These effects have been attributed to
inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs
and lithium are administered concurrently, subjects should be observed carefully
for signs of lithium toxicity.<br/>Methotrexate: NSAIDs have been
reported to competitively inhibit methotrexate accumulation in rabbit kidney
slices. This may indicate that they could enhance the toxicity of methotrexate.
Caution should be used when NSAIDs are administered concomitantly with methotrexate.<br/>Warfarin: The effects of
warfarin and NSAIDs on GI bleeding are synergistic, such that users of both
drugs together have a risk of serious GI bleeding higher than users of either
drug alone. In vitro studies have shown that, because
of its affinity for protein, 6MNA may displace other protein-bound drugs from
their binding site. Caution should be exercised when administering RELAFEN
with warfarin since interactions have been seen with other NSAIDs. Concomitant
administration of an aluminum-containing antacid had no significant effect
on the bioavailability 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 CLINICAL PHARMACOLOGY, Pharmacokinetics).<br/>Carcinogenesis, Mutagenesis: In 2-year studies conducted
in mice and rats, nabumetone had no statistically significant tumorigenic
effect. Nabumetone did not show mutagenic potential in the Ames test and mouse
micronucleus test in vivo; however, nabumetone- 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).<br/>Impairment of Fertility: Nabumetone did not impair fertility of male or female rats
treated orally at doses of 320 mg/kg/day (1,888 mg/m)
before mating.<br/>Pregnancy:<br/>Teratogenic Effects: Pregnancy
Category C. Reproductive
studies conducted in rats and rabbits have not demonstrated evidence of developmental
abnormalities. However, animal reproduction studies are not always predictive
of human response. There are no adequate, well-controlled studies in pregnant
women. RELAFEN should be used in pregnancy only if the potential benefit justifies
the potential risk to the fetus.<br/>Nonteratogenic Effects: Because of the
known effects of non-steroidal anti-inflammatory drugs on the fetal cardiovascular
system (closure of ductus arteriosus), use during pregnancy (particularly
late pregnancy) should be avoided.<br/>Labor and Delivery: In rat studies with NSAIDs, as with other drugs known to
inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed
parturition, and decreased pup survival occurred. The effects of RELAFEN on
labor and delivery in pregnant women are unknown.<br/>Nursing Mothers: It is not known whether this drug is excreted in human milk,
however 6MNA is excreted in the milk of lactating rats. Because many drugs
are excreted in human milk and because of the potential for serious adverse
reactions in nursing infants from RELAFEN, a decision should be made whether
to discontinue nursing or to discontinue the drug, taking into account the
importance of the drug to the mother.<br/>Pediatric Use: Safety and effectiveness in pediatric patients have not
been established.<br/>Geriatric Use: As with any NSAIDs, caution should be exercised in treating
the elderly (65 years and older). Of the 1,677 patients in US clinical studies
who were treated with RELAFEN, 411 patients (24%) were 65 years
or older; 22 patients (1%) were 75 years 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-US postmarketing surveillance
study of 10,800 patients treated with RELAFEN, of whom 4,577 patients
(42%) were 65 years or older.
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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 arerare. 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 g/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 RELAFEN reported with no long-term sequelae following standard emergency
treatment (i.e., activated charcoal, gastric lavage, IV H-blockers,
etc.).
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nabumetone
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RELAFEN (Tablet, Film Coated)
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Adverse reaction information was derived from blinded-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 US
clinical studies. Of the 1,677 patients who received
RELAFEN during US 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 Incidence of reported
reaction between 3% and 9%. Reactions occurring in 1% to 3% of the patients
are unmarked. Incidence<1%���Probably
Causally Related 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
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Carefully consider
the potential benefits and risks of RELAFEN and other treatment options before
deciding to use RELAFEN. Use the lowest effective dose for the shortest duration
consistent with individual patient treatment goals (see WARNINGS). RELAFEN
is indicated for relief of signs and symptoms of osteoarthritis and rheumatoid
arthritis.
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RELAFEN
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