CLINICAL PHARMACOLOGY:

Naproxen is a NSAID with analgesic and antipyretic properties. The naproxen anion inhibits prostaglandin synthesis but beyond this its mode of action is unknown.

Pharmacokinetics: Naproxen itself is rapidly and completely absorbed from the gastrointestinal tract with an in vivo bioavailability of 95%. The elimination half-life of naproxen is from 12 to 17 hours. Steady-state levels of naproxen are reached in 4 to 5 days.

Absorption: Immediate Release:  after administration of Naproxen tablets, peak plasma levels are attained in 2 to 4 hours.

When Naproxen was given to fasted subjects (n=24) in a crossover study following 1 week of dosing:

 Naproxen 500 mg bid

 C _max (µg/mL)                                                       97.4 (13%)

 T _max (hours)                                                        1.9 (61%)

 AUC _{0 - 12 hr} (µg·hr/mL)                                             767 (15%)

Distribution: Naproxen has a volume of distribution of 0.16 L/kg. At therapeutic levels naproxen is greater than 99% albumin-bound.

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

Elimination: the clearance of naproxen is 0.13 mL/min/kg. Approximately 95% of the naproxen from any dose is excreted in the urine, primarily as naproxen (less than 1%), 6-0-desmethyl naproxen (less than 1%) or their conjugates (66% to 92%).

WARNINGS:

Risk of GI ulceration, bleeding and perforation with NSAID therapy: serious gastrointestinal toxicity such as bleeding, ulceration and perforation can occur at any time, with or without warning symptoms, in patients treated chronically with NSAID therapy. symptomatic upper GI ulcers, gross bleeding or perforation appear to occur in approximately 1% of patients treated for 3 to 6 months and in about 2% to 4% of patients treated for 1 year.

PRECAUTIONS:

Renal effects: in humans, there have been reports of acute interstitial nephritis, hematuria, proteinuria and occasionally nephrotic syndrome associated with naproxen-containing products and other NSAIDs since they have been marketed.

Naproxen and its metabolites are eliminated primarily by the kidneys; therefore, the drug should be used with caution in patients with significantly impaired renal function, and the monitoring of serum creatinine and/or creatinine clearance is advised in these patients.

Hepatic function: as with other nonsteroidal anti-inflammatory drugs, borderline elevations of one or more liver tests may occur in up to 15% of patients. Although such reactions are rare, if abnormal liver tests persist or worsen, if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (eg, eosinophilia, rash, etc.), naproxen should be discontinued.

Fluid retention and edema:  peripheral edema has been observed in some patients receiving naproxen, should be used with caution in patients with fluid retention, hypertension or heart failure.

Pregnancy:  Pregnancy Category B.

Nonteratogenic effects: because of the known effect of drugs of this class on the human fetal cardiovascular system (closure of ductus arteriosus), use during third trimester should be avoided.

Nursing Mothers: use in nursing mothers should be avoided.

Pediatric Use: safety and effectiveness in pediatric patients below the age of 2 years have not been established.

Drug Interactions:

The use of NSAIDs in patients who are receiving ACE inhibitors may potentiate renal disease states. Taking the drug significantly affects prothrombin times when administered to individuals on coumarin-type anticoagulants. Similarly, patients receiving the drug and a hydantoin, sulfonamide or sulfonylurea should be observed for signs of toxicity to these drugs. Concomitant administration of naproxen and aspirin is not recommended. Inhibition of renal lithium clearance leading to increases in plasma lithium concentrations has also been reported. Naproxen and other nonsteroidal anti-inflammatory drugs can reduce the antihypertensive effect of propranolol and other beta-blockers. Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly. Caution should be used if naproxen is administered concomitantly with methotrexate.

Drug laboratory test interactions: Naproxen may decrease platelet aggregation and prolong bleeding time. This effect should be kept in mind when bleeding times are determined. The administration of naproxen may result in increased urinary values for 17-ketogenic steroids.

SIDE EFFECTS:

Incidence greater than 1% (Probable Causal Relationship):

Gastrointestinal: constipation, heartburn, abdominal pain, nausea, dyspepsia, diarrhea, stomatitis.

Central Nervous System: headache, dizziness, drowsiness, lightheadedness, vertigo

Dermatologic: itching(pruritus), skin eruptions, ecchymoses, sweating, purpura

Special Senses: tinnitus, hearing disturbances, visual disturbances

Cardiovascular: edema, dyspnea, palpitations

General: thirst

OVERDOSAGE:

Significant naproxen overdosage may be characterized by drowsiness, heartburn, indigestion, and nausea or vomiting. Should the stomach may be emptied and usual supportive measures employed. Hemodialysis does not decrease the plasma concentration of naproxen because of the high degree of its protein binding.

DOSAGE AND ADMINISTRATION:

Rheumatoid arthritis, Osteoarthritis and Ankylosing spondylitis:

Naproxen 250 mg or 500 mg twice daily 

During long-term administration, the dose of naproxen may be adjusted up or down depending on the clinical response of the patient. A lower daily dose may suffice for long-term administration.

In patients who tolerate lower doses well, the dose may be increased to naproxen 1500 mg per day for limited periods of up to 6 months when a higher level of anti-inflammatory/analgesic activity is required.

Juvenile Arthritis: the recommended total daily dose of naproxen is approximately 10 mg/kg given in 2 divided doses (ie, 5 mg/kg given twice a day).

Management of Pain, Primary Dysmenorrhea and Acute Tendonitis and Bursitis:    The recommended starting dose is 500 mg of naproxen followed by 500 mg every 12 hours.

Acute Gout: the recommended starting dose is 750 mg of Naproxen followed by 250 mg every 8 hours until the attack has subsided.

How Supplied: Each pack of Ruz-Naproxen 250 mg contains 100 tablets in 10 blisters. Each pack of Ruz-Naproxen 500 mg tablets contain 30 enteric coated tablets in a glass bottle.

storage: Store below 30°C in well-closed containers; dispense in light-resistant containers.

For more information please refer to:

         PDR 2000, page 2631-4

         USPDI for Professional Health Care, 2004, Page 374-402

               Martindale 2005, Page 65-6