The absorption rate from the sustained release particulate component of NAPRELAN® Tablets is slower than that for conventional naproxen sodium tablets. It is this prolongation of drug absorption processes which maintains plasma levels and allows for once daily dosing.

Food Effects

No significant food effects were observed when twenty-four subjects were given a single dose of NAPRELAN® Tablets 500 mg either after an overnight fast or 30 minutes after a meal. In common with conventional naproxen and naproxen sodium formulations, food causes a slight decrease in the rate of naproxen absorption following NAPRELAN® Tablets administration.

Distribution

Naproxen has a volume of distribution of 0.16 L/kg. At therapeutic levels, naproxen is greater than 99% albumin-bound. At doses of naproxen greater than 500 mg/day, there is a less than proportional increase in plasma levels due to an increase in clearance caused by saturation of plasma protein binding at higher doses. However the concentration of unbound naproxen continues to increase proportionally to dose. NAPRELAN® Tablets exhibit similar dose proportional characteristics.

Metabolism

Naproxen is extensively metabolized to 6-0-desmethyl naproxen and both parent and metabolites do not induce metabolizing enzymes.

Elimination

The elimination half-life of NAPRELAN® Tablets and conventional naproxen is approximately 15 hours. Steady state conditions are attained after 2-3 doses of NAPRELAN® Tablets. Most of the drug is excreted in the urine, primarily as unchanged naproxen (less than 1%), 6-0-desmethyl naproxen (less than 1%) and their glucuronide or other conjugates (66-92%). A small amount ( < 5%) of the drug is excreted in the feces. The rate of excretion has been found to coincide closely with the rate of clearance from the plasma. In patients with renal failure, metabolites may accumulate.

Special Populations

Pediatric Use

No pediatric studies have been performed with NAPRELAN® Tablets, thus safety of NAPRELAN® Tablets in pediatric populations has not been established.

Renal Insufficiency

Naproxen pharmacokinetics have not been determined in subjects with renal insufficiency. Given that naproxen is metabolized and conjugates are primarily excreted by the kidneys, the potential exists for naproxen metabolites to accumulate in the presence of renal insufficiency. Elimination of naproxen is decreased in patients with severe renal impairment. Naproxen-containing products are not recommended for use in patients with moderate to severe and severe renal impairment (creatinine clearance < 30mL/min)(see WARNINGS – Renal Effects).

Clinical Studies

Rheumatoid Arthritis

The use of NAPRELAN® Tablets for the management of the signs and symptoms of rheumatoid arthritis was assessed in a 12 week double-blind, randomized, placebo and active-controlled study in 348 patients. Two NAPRELAN®500 mg tablets (1000 mg) once daily and naproxen 500 mg tablets twice daily (1000 mg) were more effective than placebo. Clinical effectiveness was demonstrated at one week and continued for the duration of the study.

Osteoarthritis

The use of NAPRELAN® Tablets for the management of the signs and symptoms of osteoarthritis of the knee was assessed in a 12 week double-blind, placebo and active-controlled study in 347 patients. Two NAPRELAN® 500 mg tablets (1000 mg) once daily and naproxen 500 mg tablets twice daily (1000 mg) were more effective than placebo. Clinical effectiveness was demonstrated at one week and continued for the duration of the study.

Analgesia

The onset of the analgesic effect of NAPRELAN® Tablets was seen within 30 minutes in a pharmacoki-netic/pharmacodynamic study of patients with pain following oral surgery. In controlled clinical trials, naproxen has been used in combination with gold, D-penicillamine, methotrexate and corticosteroids. Its use in combination with salicylate is not recommended because there is evidence that aspirin increases the rate of excretion of naproxen and data are inadequate to demonstrate that naproxen and aspirin produce greater improvement over that achieved with aspirin alone. In addition, as with other NSAIDs the combination may result in higher frequency of adverse events than demonstrated for either product alone.

Special Studies

In a double-blind randomized, parallel group study, 19 subjects received either two NAPRELAN® 500 mg tablets (1000 mg) once daily or naproxen 500 mg tablets (1000 mg) twice daily for 7 days. Mucosal biopsy scores and endoscopic scores were lower in the subjects who received NAPRELAN® Tablets. In another double-blind, randomized, crossover study, 23 subjects received two NAPRELAN® 500 mg tablets (1000 mg) once daily, naproxen 500 mg tablets (1000 mg) twice daily and aspirin 650 mg four times daily (2600 mg) for 7 days each. There were significantly fewer duodenal erosions seen with NAPRELAN® Tablets than with either naproxen or aspirin. There were significantly fewer gastric erosions with both NAPRELAN®Tablets and naproxen than with aspirin. The clinical significance of these findings is unknown.

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