Nabumetone (Page 2 of 7)

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 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 nabumetone generally is not necessary in patients with mild renal insufficiency (≥ 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 1,000 mg or 2,000 mg of nabumetone daily when compared to either placebo-treated or non-treated subjects. In contrast, aspirin 3,600 mg daily produced an increase in fecal blood loss when compared to subjects who received nabumetone, 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 nabumetone daily or naproxen 250 mg or 500 mg twice daily for 3 to 12 weeks, treatment with nabumetone 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 nabumetone daily or piroxicam 10 mg to 20 mg for 7 to 10 days, there were fewer patients treated with nabumetone with endoscopically detected lesions. In 3 trials of a total of 47 patients on 1,000 mg of nabumetone 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 nabumetone daily to ibuprofen 2,400 mg/day and ibuprofen 2,400 mg/day plus misoprostol 800 mcg/day. The results showed that patients treated with nabumetone 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.

Other

In 1 week, repeat-dose studies in healthy volunteers, 1,000 mg of nabumetone 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 1,000 mg/day administered at night was comparable to naproxen 500 mg/day and to aspirin 3,600 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 1,000 mg/day administered at night, was comparable to naproxen 500 mg/day and to aspirin 3,600 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 1,000 mg/day administered nightly; total daily dosages up to 2,000 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 2: Clinical Double-Blinded and Open-Labeled Trials of Nabumetone in Osteoarthritis and Rheumatoid Arthritis
Dose of Nabumetone Number of Patients Mean/Mode Duration of Treatment (yr)
OA RA OA RA
500 mg 17 6 0.4/– 0.2/–
1,000 mg 917 701 1.2/1 1.4/1
1,500 mg 645 224 2.3/1 1.7/1
2,000 mg 15 100 0.6/1 1.3/1

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 1,000 mg; therefore, after observing the response to initial therapy, the dose should be adjusted to meet individual patients’ requirements.

INDICATIONS AND USAGE

Carefully consider the potential benefits and risks of nabumetone tablets and other treatment options before deciding to use nabumetone tablets. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS).

Nabumetone tablets are indicated for relief of signs and symptoms of osteoarthritis and rheumatoid arthritis.

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