Nabumetone: Package Insert and Label Information

NABUMETONE- nabumetone tablet
Eon Labs, Inc.

Rx Only

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).

Gastrointestinal Risk

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).

DESCRIPTION

Nabumetone is a naphthylalkanone designated chemically as 4-(6-methoxy-2-naphthalenyl)-2-butanone. It has the following structure:

Chemical Structure 1

nabumetone

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.

Tablets for Oral Administration

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.

CLINICAL PHARMACOLOGY

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.

Chemical Structure 2

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.

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 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.

Table Mean Pharmacokinetic Parameters of Nabumetone Active Metabolite (6MNA) at Steady State Following Oral Administration of 1000-mg or 2000-mg Doses of Nabumetone

Abbreviation

(units)

Young Adults

Mean ± SD

1000 mg

n = 31

Young Adults

Mean ± SD

2000 mg

n = 12

Elderly

Mean ± SD

1000 mg

n = 27

tmax (hours)

t1⁄2 (hours)

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)

Active Metabolite Chart
(click image for full-size original)

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:

–nabumetone, unchanged

not detectable

–6-methoxy-2-naphthylacetic acid (6MNA), unchanged

less than 1%

–6MNA, conjugated

11%

–6-hydroxy-2-naphthylacetic acid (6HNA), unchanged

5%

–6HNA, conjugated

7%

–4-(6-hydroxy-2-naphthyl)-butan-2-ol, conjugated

9%

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 clearance of 6MNA is 20 mL/min to 30 mL/min. and the elimination half-life is approximately 24 hours.

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.)

Renal Insufficiency

In moderate renal insufficiency patients (creatinine clearance 30 mL/min 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 less than 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 nabumetone generally is not necessary in patients with mild renal insufficiency (greater than or equal to 50 mL/min). Caution should be used in prescribing nabumetone to patients with moderate or severe renal insufficiency. The maximum starting doses of nabumetone 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).

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).

Special Studies

Gastrointestinal

Nabumetone was compared to aspirin in inducing gastrointestinal blood loss. Food intake was not monitored. Studies utilizing 51 Cr-tagged red blood cells in healthy males showed no difference in fecal blood loss after 3 or 4 weeks’ administration of nabumetone 1000 mg or 2000 mg daily when compared to either placebo-treated or nontreated subjects. In contrast, aspirin 3600 mg daily produced an increase in fecal blood loss when compared to the nabumetone-treated, placebo-treated or nontreated 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 clinical relevance of these endoscopy trials, i.e., either GI symptoms or serious GI 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 nabumetone 1000 mg daily or naproxen 250 mg or 500 mg twice daily for 3 to 12 weeks, nabumetone treatment resulted in fewer patients with endoscopically detected lesions (greater than 3 mm). In 2 trials a total of 101 patients on nabumetone 1000 mg or 2000 mg daily or piroxicam 10 mg to 20 mg for 7 to 10 days, there were fewer nabumetone patients with endoscopically detected lesions. In 3 trials of a total of 47 patients on nabumetone 1000 mg 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 nabumetone 1000 mg/day to ibuprofen 2400 mg/day and ibuprofen 2400 mg/day plus misoprostol 800 mcg/day. The results showed that patients treated with nabumetone had a lower number of endoscopically detected lesions (greater than 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.

Other

In 1-week, repeat-dose studies in healthy volunteers, nabumetone 1000 mg 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.

CLINICAL TRIALS

Osteoarthritis

The use of nabumetone in relieving the signs and symptoms of osteoarthritis (OA) was assessed in double-blind, controlled trials in which 1,047 patients were treated for 6 weeks to 6 months. In these trials, nabumetone 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 nabumetone in relieving the signs and symptoms of rheumatoid arthritis (RA) was assessed in double-blind, randomized, controlled trials in which 770 patients were treated for 3 weeks to 6 months. Nabumetone, in a dose of 1000 mg/day administered at night was comparable to naproxen 500 mg/day and to aspirin 3600 mg/day.

In controlled clinical trials of rheumatoid arthritis patients, nabumetone has been used in combination with gold, d-penicillamine and corticosteroids.

Patient Exposure in Clinical Trials of Osteoarthritis and Rheumatoid Arthritis

In clinical trials with osteoarthritis and rheumatoid arthritis patients, most patients responded to nabumetone in doses of 1000 mg/day administered nightly; total daily dosages up to 2000 mg were used. In open-labeled studies, 1,490 patients were permitted dosage 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-labeled studies. The following table provides patient exposure to doses used in the U.S. clinical trials:

Table Clinical Double-Blind and Open-Labeled Trials of Nabumetone in Osteoarthritis and Rheumatoid Arthritis

Nabumetone

Dose

Number of Patients

Mean/Mode

Duration of Treatment (yrs.)

QA

RA

QA

RA

500 mg

1000 mg

1500 mg

2000 mg

17

917

645

15

6

701

224

100

0.4/-

1.2/1

2.3/1

0.6/1

0.2/-

1.4/1

1.7/1

1.3/1

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