NABUMETONE- nabumetone tablet
Eon Labs, Inc.
Cardiovascular Thrombotic Events
- Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use (see WARNINGS and PRECAUTIONS).
- Nabumetone tablets are contraindicated in the setting of coronary artery bypass graft (CABG) surgery (see CONTRAINDICATIONS and WARNINGS).
- NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal (GI) events (see WARNINGS).
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.
Each oval-shaped, film-coated tablet contains 500 mg or 750 mg of nabumetone. Inactive ingredients consist of colloidal silicon dioxide, croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, titanium dioxide, polyethylene glycol 400, polysorbate 80 and sodium lauryl sulfate.
Nabumetone 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.
6-methoxy-2-naphthylacetic acid (6MNA)
It is acidic and has an n-octanol:phosphate buffer partition coefficient of 0.5 at pH 7.4.
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 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 nabumetone tablets, 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 1000 mg 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.
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.
Co-administration 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.
Mean ± SD
n = 31
Mean ± SD
n = 12
Mean ± SD
n = 27
CLss /F (mL/min.)
Vdss /F (L)
3.0 (1 to 12)
22.5 ± 3.7
26.1 ± 17.3
55.4 ± 26.4
2.5 (1 to 8)
26.2 ± 3.7
21 ± 4
53.4 ± 11.3
4 (1 to 10)
29.8 ± 8.1
18.6 ± 13.4
50.2 ± 25.3
The simulated curves in the graph below illustrate the range of active metabolite plasma concentrations that would be expected from 95% of patients following 1000-mg to 2000-mg doses to steady state. The cross-hatched area represents the expected overlap in plasma concentrations due to intersubject variation following oral administration of 1000 mg to 2000 mg of nabumetone.
Nabumetone Active Metabolite (6MNA) Plasma Concentrations at Steady State Following Once-Daily Dosing of Nabumetone
1000 mg (n=31) 2000 mg (n=12)
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:
–6-methoxy-2-naphthylacetic acid (6MNA), unchanged
less than 1%
–6-hydroxy-2-naphthylacetic acid (6HNA), unchanged
–O -desmethyl-nabumetone, conjugated
–unidentified minor metabolites
Total % Dose:
Following oral administration of dosages of 1000 mg to 2000 mg to steady state, the mean plasma clearance of 6MNA is 20 mL/min to 30 mL/min. and the elimination half-life is approximately 24 hours.
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