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Naprelan

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Naprelan

CLINICAL PHARMACOLOGY

Naproxen is a nonsteroidal anti-inflammatory drug (NSAID), with analgesic and antipyretic properties. As with other NSAIDs, its mode of action is not fully understood; however, its ability to inhibit prostaglandin synthesis may be involved in the anti-inflammatory effect.

Pharmacokinetics

Although naproxen itself is well absorbed, the sodium salt form is more rapidly absorbed resulting in higher peak plasma levels for a given dose. Approximately 30% of the total naproxen sodium dose in NAPRELAN® (naproxen sodium) Tablets is present in the dosage form as an immediate release component. The remaining naproxen sodium is coated as microparticles to provide sustained release properties. After oral administration, plasma levels of naproxen are detected within 30 minutes of dosing, with peak plasma levels occurring approximately 5 hours after dosing. The observed terminal elimination half-life of naproxen from both immediate release naproxen sodium and NAPRELAN® (naproxen sodium) Tablets is approximately 15 hours. Steady state levels of naproxen are achieved in 3 days and the degree of naproxen accumulation in the blood is consistent with this.

Plasma Naproxen Concentrations Mean of 24 Subjects (+/-2SD)

(Steady State, Day 5)

Plasma Naproxen Concentrations Mean of 24 Subjects (+/-2SD) (Steady State, Day 5) - illustration

Pharmacokinetic Parameters at Steady State Day 5 (Mean of 24 Subjects)

Parameter (units) naproxen 500mg Q12h/ 5days (1000 mg) NAPRELAN® 2 x 500 mg tablets (1000 mg) Q24h/5 days
  Mean SD Range Mean SD Range
AUC 0-24 (mcgxh/mL) 1446 168 1167 - 1858 1448 145 1173 - 1774
Cmax (mcg/mL) 95 13 71 - 117 94 13 74 - 127
Cavg (mcg/mL) 60 7 49 - 77 60 6 49 - 74
Cmin (mcg/mL) 36 9 13 - 51 33 7 23 - 48
Tmax (hrs) 3 1 1 - 4 5 2 2-10
 Absorption

Naproxen itself is rapidly and completely absorbed from the GI tract with an in vivo bioavailability of 95%. Based on the pharmacokinetic profile, the absorption phase of NAPRELAN® (naproxen sodium) Tablets occurs in the first 4-6 hours after administration. This coincides with disintegration of the tablet in the stomach, the transit of the sustained release microparticles through the small intestine and into the proximal large intestine. An in vivo imaging study has been performed in healthy volunteers which confirms rapid disintegration of the tablet matrix and dispersion of the microparticles.

The absorption rate from the sustained release particulate component of NAPRELAN® (naproxen sodium) 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® (naproxen sodium) 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® (naproxen sodium) 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® (naproxen sodium) 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® (naproxen sodium) Tablets and conventional naproxen is approximately 15 hours. Steady state conditions are attained after 2-3 doses of NAPRELAN® (naproxen sodium) 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® (naproxen sodium) Tablets, thus safety of NAPRELAN® (naproxen sodium) 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® (naproxen sodium) 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® (naproxen sodium) 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® (naproxen sodium) 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® (naproxen sodium) 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® (naproxen sodium) 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® (naproxen sodium) 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® (naproxen sodium) Tablets. In another double-blind, randomized, crossover study, 23 subjects received two NAPRELAN® (naproxen sodium) 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® (naproxen sodium) Tablets than with either naproxen or aspirin. There were significantly fewer gastric erosions with both NAPRELAN® (naproxen sodium) Tablets and naproxen than with aspirin. The clinical significance of these findings is unknown.

Last reviewed on RxList: 12/14/2007
This monograph has been modified to include the generic and brand name in many instances.

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