June 26, 2016
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Naprelan

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Naprelan

CLINICAL PHARMACOLOGY

Mechanism Of Action

Naproxen has analgesic, anti-inflammatory, and antipyretic properties.

The mechanism of action of NAPRELAN, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2).

Naproxen sodium is a potent inhibitor of prostaglandin synthesis in vitro. Naproxen sodium concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because naproxen sodium is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues.

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 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 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 - Illustration

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

Parameter (units) naproxen 500 mg Q12h/5 days (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
T max (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 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 that confirms rapid disintegration of the tablet matrix and dispersion of the microparticles.

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 that 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.

Elimination

Metabolism

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

Excretion

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.

Specific Populations

Pediatric

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

Hepatic Impairment

Chronic alcoholic liver disease and probably other diseases with decreased or abnormal plasma proteins (albumin) reduce the total plasma concentration of naproxen, but the plasma concentration of unbound naproxen is increased. Caution is advised when high doses are required and some adjustment of dosage may be required in these patients. It is prudent to use the lowest effective dose.

Renal Impairment

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 AND PRECAUTIONS].

Drug Interaction Studies

Aspirin: When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 1 for clinically significant drug interactions of NSAIDs with aspirin [see DRUG INTERACTIONS].

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 pharmacokinetic/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

Last reviewed on RxList: 6/7/2016
This monograph has been modified to include the generic and brand name in many instances.

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