NAME:RAS EMIL SAZURA BINTI RAZALI

NIM:C11111877
COX-2 INHIBITOR:NABUMETONE
Nabumetone is a non-steroidal anti-inflammatory drug (NSAID), the only 1naphthaleneacetic acid derivative. As found with previous NSAIDs, nabumetone's active
metabolite inhibits the cyclooxygenase enzyme and preferentially blocks COX-2 activity
(which is indirectly responsible for the production of inflammation and pain during arthritis).
The active metabolite of nabumetone is felt to be the compound primarily responsible for
therapeutic effect. Comparatively, the parent drug is a poor inhibitor of COX-2 byproducts,
particularly prostaglandins. It may be less nephrotoxic than indomethacin.

Indication
Treating rheumatoid arthritis or osteoarthritis.
Contraindication
Aspirin allergy. 3rd trimester pregnancy. Coronary artery bypass graft surgery.
Side effect
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 (nabumetone) 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 Chest pain, weakness, shortness of breath, slurred
speech, problems with vision or balance,black, bloody, or tarry stools,coughing up blood or
vomit that looks like coffee grounds,swelling or rapid weight gain,urinating less than usual or
not at all.
This drug may rarely cause serious (possibly fatal) liver disease. If you notice any of the
following highly unlikely but very serious side effects, stop taking nabumetone and consult
your doctor or pharmacist immediately: dark urine, persistent nausea/vomiting, severe
stomach/abdominal pain, yellowing eyes or skin.
A very serious allergic reaction to this drug is rare. However, get medical help right away if
you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling
(especially of the face/tongue/throat), severe dizziness, trouble breathing.

Dosage
Dosage is based on your medical condition and response to treatment. To minimize side
effect risks (such as stomach bleeding), use this medication at the lowest effective dose for
the shortest possible length of time.
Adult Dose for Nabumetone:
Initially 1g once daily; max 2g/day in 1 or 2 divided doses. Renal insufficiency (CrCl 30
49mL/min): initial max 750mg once daily, may increase to 1.5g/day; (CrCl <30mL/min):
initial max 500mg once daily, may increase to 1g/day.
Special precaution
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 65 years of age) and
UK postmarketing 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.
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.
Pharmacokinetic
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 (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 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.
Pharmacodynamics
Nabumetone is a naphthylalkanone. Is is a non-selective prostaglandin G/H synthase (a.k.a.
cyclooxygenase or COX) inhibitor that acts on both prostaglandin G/H synthase 1 and 2
(COX-1 and -2). Prostaglandin G/H synthase catalyzes the conversion of arachidonic acid to
prostaglandin G2 and prostaglandin G2 to prostaglandin H2. Prostaglandin H2 is the
precursor to a number of prostaglandins involved in fever, pain, swelling, inflammation, and
platelet aggregation. The parent compound is a prodrug that undergoes hepatic
biotransformation to the active compound, 6-methoxy-2-naphthylacetic acid (6MNA). The
analgesic, antipyretic and anti-inflammatory effects of NSAIDs occur as a result of decreased
prostaglandin synthesis.