Naproxen has demonstrated anti-inflammatory, analgesic and antipyretic properties in classical animal test systems. In patients with rheumatoid arthritis, the anti-inflammatory action has been shown by a reduction in joint swelling, pain, and duration of morning stiffness, and by enhanced grip strength and increased mobility. It exhibits an anti-inflammatory effect even in adrenalectomized animals, and therefore its action is not mediated through the pituitary-adrenal axis. It is not a corticosteroid.

During clinical trials, naproxen has been found to be less likely to cause gastrointestinal bleeding in doses usually used than is ASA.

Clinical trials in man have shown the clinical activity of 500 mg of naproxen daily to be similar to that of 3.6 g of ASA daily.

From clinical trials, it appears that naproxen enteric-coated tablets have reduced potential for severe complaints when compared to standard naproxen.

Naproxen is rapidly and completely absorbed from the gastrointestinal tract. After oral administration of naproxen, peak plasma levels of naproxen anion are attained in 2 to 4 hours, with steady-state conditions normally achieved after 4 to 5 doses. Plasma naproxen levels and areas under plasma concentration vs time curves increased linearly with dose increments up to 500 mg twice a day, but larger doses resulted in a plateau effect. The time to reach peak plasma concentration following rectal administration of naproxen 500 mg suppository relative to the oral tablet was not significantly different. 0 to 24 hour areas under the plasma concentration versus time curves for the 500 mg dose of either naproxen tablets or suppository were similar. The mean biological half-life of the anion in humans is approximately 13 hours, and at therapeutic levels it is greater than 99% albumin bound. Approximately 95% of the dose is excreted in the urine, primarily as naproxen, 6-0-desmethyl naproxen or their conjugates. The rate of excretion has been found to coincide closely with the rate of drug disappearance from the plasma. The drug does not induce metabolizing enzymes.

In children with rheumatic diseases aged between 5 to 16 years, naproxen reached peak plasma levels 2 to 4 hours following oral dosing and the mean plasma half-life was 11.5 to 14.1 hours. Naproxen suspension was found to have similar bioavailability to the naproxen tablets in 2 single dose studies done in 24 healthy male volunteers. No clinically significant differences in tolerance were reported between the 2 dosage forms.

When naproxen is administered in the sustained release form (Naprosyn SR), the peak plasma levels are delayed and the maximum plasma concentrations are reduced compared to those seen with standard release formulations of naproxen. The minimum plasma concentrations, at steady state, are equivalent between naproxen sustained release given once a day and the corresponding standard dosage given twice a day. The peak to trough plasma concentration ratio of 2.2 and 2.6 observed with the standard tablet formulation (375 mg b.i.d. and 500 mg b.i.d. respectively) is reduced to 1.6 and 1.8 with 750 and 1000 mg naproxen sustained release tablets respectively, resulting in smaller fluctuations in plasma concentrations of naproxen with the naproxen sustained release tablets.

The average T_max of naproxen in subjects receiving the 1000 mg sustained release tablet immediately after a high fat meal did not differ significantly when compared to the fasting state (7.7 hours postprandial; 9.7 hours fasting). The average C_max increased significantly from 63.1 µg/mL (fasting) to 86.1 µg/mL (postprandial). This increase in C_max was still lower than that observed with the 1000 mg dose of standard naproxen tablets. Based upon the 95% confidence interval, the AUC's were equivalent when the SR tablet was administered under fasting and nonfasting conditions.

A 28 day study of chromium-51-labeled red blood cell loss in feces was conducted with the 750 mg sustained release naproxen tablets in 20 patients. There was no statistically significant difference in red blood cell loss between patients 60 years of age or younger and those over 60.

Naproxen enteric-coated tablets are designed to be dispersed and dissolved in the small bowel rather than the stomach, so the absorption is delayed until the stomach is emptied. Naproxen enteric-coated tablets were bioequivalent to the standard 375 and 500 mg tablets, except for a substantially increased time to peak plasma concentration (T_max). The average maximum plasma concentration (C_max) following the 375 mg, 2×250 mg and 500 mg enteric-coated tablets were 47.9, 58.2 and 60.7 µg/mL, while the C_max following the 375 and 500 mg standard immediate release tablets were 46.6 and 63.1 µg/mL, respectively. The T_max's were 4.5, 4.2 and 4.2 hours for the respective enteric-coated formulations as compared to 2.3 and 2.6 hours after standard naproxen tablets. At steady state (multiple dosing) naproxen enteric coated and the standard naproxen were equivalent to each other with respect to C_max, C_ave, C_max/C_ave, 0 to 12 hours AUC and half-life. In addition, fluctuation in plasma levels about C_ave were considerably less with naproxen enteric-coated tablets as compared to the standard naproxen (49.3 vs 85.3%). Administration of 500 mg enteric-coated naproxen tablets with food and antacid did not alter the extent of absorption of naproxen as compared to the fasting condition. However, antacid treatment resulted in a higher C_max (70.7 vs 58.5 µg/mL) and earlier T_max (5.2  vs 8.7 hours) in comparison to the fasting condition. Relative to the fasting state, the average T_max was delayed following a high fat meal (5.6 to 8.7 hours fasting, 9.2 to 10.8 hours post-prandial) while the average C_max and AUC were bioequivalent.

Treatment of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis and juvenile rheumatoid arthritis.

Naproxen is also indicated for the relief of minor aches and pains in muscles, bones and joints, mild to moderate pain accompanied by inflammation in musculoskeletal injuries (sprains and strains) and primary dysmenorrhea.

Modified release formulations of naproxen (i.e., enteric-coated and sustained release) are not recommended for initial treatment of acute pain because the absorption of naproxen is delayed.

In patients with active peptic ulcers, a history of recurrent ulceration, or active inflammatory diseases of the gastro intestinal tract. Naproxen is also contraindicated in patients who have known or suspected hypersensitivity to it or to naproxen sodium or to other non steroidal anti inflammatory drugs. The potential for cross reactivity between different NSAIDs must be kept in mind. Naproxen should not be given to patients with the complete or partial syndrome of nasal polyps, or in whom asthma, anaphylaxis, rhinitis, urticaria, or other allergic manifestations are precipitated by ASA or other nonsteroidal anti inflammatory drugs. Fatal anaphylactoid reactions have occurred in such individuals. As well, individuals with the above medical problems are at risk of a severe reaction even if they have taken NSAIDs in the past without any adverse effects.

Naproxen is contraindicated in patients with significant hepatic impairment, active liver disease and in patients with severely impaired or deteriorating renal function (creatinine clearance <30mL/min or 0.5 mL/s). Individuals with lesser degrees of renal impairment are at risk of deterioration of their renal function when prescribed NSAIDs and must be monitored. Naproxen is not recommended for use with other NSAIDs because of the absence of any evidence demonstrating synergistic benefits and the potential for additive side effects.

Naproxen is contraindicated in children under 2 years of age since safety in this age group has not been established.

Serious gastrointestinal toxicity, such as peptic ulceration, perforation and gastrointestinal bleeding, sometimes severe and occasionally fatal can occur at any time, with or without symptoms in patients treated with NSAIDs including naproxen.

Minor upper gastrointestinal problems, such as dyspepsia, are common, usually developing early in therapy. Physicians should remain alert for ulceration and bleeding in patients treated with NSAIDs, even in the absence of previous gastrointestinal tract symptoms.

In patients observed in clinical trials of such agents, symptomatic upper gastrointestinal 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. The risk continues beyond 1 year and possibly increases. The incidence of these complications increases with increasing dose.

Naproxen should be given under close medical supervision to patients prone to gastrointestinal tract irritation particularly those with a history of peptic ulcer, diverticulosis or other inflammatory disease of the gastrointestinal tract such as ulcerative colitis and Crohn's disease. In these cases the physician must weigh the benefits of treatment against the possible hazards.

Physicians should inform patients about the signs and/or symptoms of serious gastrointestinal toxicity and instruct them to contact a physician immediately if they experience persistent dyspepsia or other symptoms or signs suggestive of gastrointestinal ulceration or bleeding.

Because serious gastrointestinal tract ulceration and bleeding can occur without warning symptoms, physicians should follow chronically treated patients by checking their hemoglobin periodically and by being vigilant for the signs and symptoms of ulceration and bleeding and should inform the patients of the importance of this follow-up.

If ulceration is suspected or confirmed, or if gastrointestinal bleeding occurs, naproxen should be discontinued immediately, appropriate treatment instituted and the patient monitored closely.

No studies, to date, have identified any group of patients not at risk of developing ulceration and bleeding. A prior history of serious gastrointestinal events and other factors such as excess alcohol intake, smoking, age, female gender and concomitant oral steroid and anticoagulant use have been associated with increased risk.

Patients older than 65 years and frail or debilitated patients are more susceptible to a variety of adverse reactions from NSAIDs: the incidence of these adverse reactions increases with dose and duration of treatment. In addition, these patients are less tolerant to the effects of ulceration and bleeding. Most reports of fatal gastrointestinal events are in this population. Older patients are also at risk of lower esophageal ulceration and bleeding.

For such patients, consideration should be given to a starting dose lower than the one usually recommended, with individual adjustment when necessary and under close supervision. See Precautions for further advice.

Cross-sensitivity: Patients sensitive to any one of the nonsteroidal anti-inflammatory drugs may be sensitive to any of the other NSAIDs also.

Aseptic Meningitis: In occasional cases, with some NSAIDs, the symptoms of aseptic meningitis (stiff neck, severe headaches, nausea and vomiting, fever or clouding of consciousness) have been observed. Patients with autoimmune disorders (systemic lupus erythematosus, mixed connective tissues diseases, etc.) seem to be predisposed. Therefore, in such patients, the physician must be vigilant to the development of this complication.

Pregnancy and Labor: Naproxen's safety in pregnancy and lactation has not been established, and its use is therefore not recommended. Reproduction studies have been performed in rats, rabbits and mice. In rats, pregnancy was prolonged when naproxen was given before the onset of labor, and when given after the delivery process had begun, labor was protracted. Similar results have been found with other NSAIDs, and the evidence suggests that this may be due to decreased uterine contractility resulting from the inhibition of prostaglandin synthesis. This may also increase the risk for uterine hemorrhage. Moreover, because of the known effect of drugs of this class on the human fetal cardiovascular system (closure of ductus arteriosus), use during late pregnancy should be avoided. Naproxen readily crosses the placental barrier. It has also been found in the milk of lactating women at a concentration approximately 1% of that found in the plasma.

See Pregnancy.

The use of naproxen, as with any drug known to inhibit cyclooxygenase/prostaglandin synthesis, may impair fertility and is not recommended in women attempting to conceive. In women who have difficulty conceiving or are undergoing investigation of infertility, withdrawal of naproxen should be considered.

Naproxen should not be used concomitantly with the related drug naproxen sodium since they both circulate in plasma as the naproxen anion.

Gastrointestinal System: There is no definitive evidence that the concomitant administration of histamine H₂ -receptor antagonists and/or antacids will either prevent the occurrence of gastrointestinal side effects or allow the continuation of naproxen therapy when and if these adverse reactions appear.

Renal Function: Long-term administration of NSAIDs to animals has resulted in renal papillary necrosis and other abnormal renal pathology. In humans, there have been reports of acute interstitial nephritis with hematuria, proteinuria, and occasionally nephrotic syndrome.

A second form of renal toxicity has been seen in patients with prerenal conditions leading to the reduction in renal blood flow or blood volume, where the renal prostaglandins have a supportive role in the maintenance of renal perfusion. In these patients, administration of a NSAID may cause a dose-dependent reduction in prostaglandin formation and may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, extracellular volume depletion, sodium restrictions, heart failure, liver dysfunction, those taking diuretics, and the elderly. Assessment of renal function in these patients before and during therapy with naproxen is recommended. Discontinuation of nonsteroidal anti-inflammatory therapy is typically followed by recovery to the pretreatment state.

Naproxen and its metabolites are eliminated primarily by the kidneys, therefore, the drug should be used with great caution in patients with impaired renal function or a history of kidney disease, because naproxen is an inhibitor of prostaglandin biosynthesis. In these cases, utilization of lower doses of naproxen should be considered and patients carefully monitored.

Naproxen should not be used chronically in patients having baseline creatinine clearance less than 20 mL/minute. During long-term therapy, kidney function should be monitored periodically.

Genitourinary Tract: Some NSAIDs are known to cause persistent urinary symptoms (bladder pain, dysuria, urinary frequency), hematuria or cystitis. The onset of these symptoms may occur at any time after the initiation of therapy with an NSAID. Some cases have become severe on continued treatment. Should urinary symptoms occur, treatment with naproxen must be stopped immediately to obtain recovery. This should be done before any urological investigations or treatments are carried out.

Hepatic Function: As with other NSAIDs, borderline elevations of one or more liver function tests may occur in up to 15% of patients (less than 1% with naproxen). These abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy. A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of more severe hepatic reaction while on therapy with this drug. Severe hepatic reactions including jaundice and cases of fatal hepatitis have been reported with NSAIDs.

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 (e.g., eosinophilia, rash, etc.), this drug should be discontinued.

During long-term therapy, liver function tests should be monitored periodically. If there is a need to prescribe this drug in the presence of impaired liver function, it must be done under strict observation.

Chronic alcoholic liver disease and probably also other forms of cirrhosis reduce the total plasma concentration of naproxen, but the plasma concentration of unbound naproxen is increased. The implication of this finding for naproxen dosing is unknown, but caution is advised when high doses are required. It is prudent to use the lowest effective dose.

Steroids: If steroid dosage is reduced or eliminated during therapy, the steroid dosage should be reduced slowly and the patients must be observed closely for any evidence of adverse effects, including adrenal insufficiency and exacerbation of symptoms of arthritis.

Fluid and Electrolyte Balance: Peripheral edema has been observed in some patients receiving naproxen. Therefore, as with many other NSAIDs, the possibility of precipitating congestive heart failure in elderly patients or those with compromised cardiac function should be borne in mind. Although sodium retention has not been reported in metabolic studies, the drug should be used with caution in patients with fluid retention, hypertension or heart failure.

Naproxen formulated as a suspension (25 mg/mL) contains sodium chloride (20 mg/mL). This should be considered in patients whose overall intake of sodium must be restricted.

With NSAID treatment, there is a potential risk of hyperkalemia particularly in patients with conditions such as diabetes mellitus or renal failure; elderly patients; or in patients receiving concomitant therapy with beta adrenergic blockers, angiotensin converting enzyme inhibitors or some diuretics. Serum electrolytes should be monitored periodically during long-term therapy, especially in those patients who are at risk.

Hematology: Drugs inhibiting prostaglandin biosynthesis do interfere with platelet function to varying degrees; therefore, patients who may be adversely affected by such an action should be carefully observed when naproxen is administered.

Blood dyscrasias (such as neutropenia, leukopenia, thrombocytopenia, aplastic anemia and agranulocytosis) associated with the use of NSAIDs are rare (all less than 1% with naproxen), but could be with severe consequences.

Patients with initial hemoglobin values of 10 g or less who are to receive long-term therapy should have hemoglobin values determined frequently.

Infection: The anti-inflammatory, antipyretic and analgesic effects of naproxen may mask the usual signs of infection.

Ophthalmology: Blurred and/or diminished vision has been reported with the use of naproxen and other NSAIDs. In rare cases, adverse ocular disorders including papillitis, retrobulbar optic neuritis and papilledema have been reported in users of NSAIDs including naproxen, although a cause and effect relationship cannot be established. If such symptoms develop, this drug should be discontinued and an ophthalmologic examination performed; ophthalmic examination should be carried out at periodic intervals in any patient receiving this drug for an extended period of time.

Central Nervous System: Some patients may experience drowsiness, dizziness, vertigo insomnia or depression with the use of naproxen. If patients experience these side effects, they should exercise caution in carrying out activities that require alertness.

Hypersensitivity: Anaphylactoid reactions to naproxen or naproxen sodium, whether of the true allergic type or the pharmacologic idiosyncratic (e.g., ASA syndrome) type, usually but not always occur in patients with a known history of such reactions. Therefore, careful questioning of patients for such things as asthma, nasal polyps, urticaria, and hypotension associated NSAIDs before starting therapy is important. In addition, if such symptoms occur during therapy, treatment should be discontinued.

Dermatology: If skin fragility, blistering or other symptoms suggestive of pseudoporphyria occur, treatment should be discontinued and the patient monitored.

One study indicates that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly. The implication of this finding for naproxen dosing is unknown, but caution is advised when high doses are required. As with other drugs used in the elderly, it is prudent to use the lowest effective dose.

ASA or other NSAIDs: The use of naproxen in addition to any other NSAID, including those over-the-counter ones (such as ASA and ibuprofen) is not recommended due to the possibility of additive side effects.

Anticoagulants: Numerous studies have shown that the concomitant use of NSAIDs and anticoagulants increases the risk of gastrointestinal adverse events such as ulceration and bleeding.

Because prostaglandins play an important role in hemostasis and NSAIDs affect platelet function, concurrent therapy of naproxen with warfarin requires close monitoring to be certain that no change in anticoagulant dosage is necessary.

Albumin-bound Drugs: The naproxen anion may displace from their binding sites other drugs which are also albumin-bound and may lead to drug interactions. For example, in patients receiving bishydroxycoumarin or warfarin, the addition of naproxen could prolong the prothrombin time. These patients should therefore be under careful observation. Similarly, patients receiving naproxen and a hydantoin, sulfonamide or sulfonylurea should be observed for adjustment of dose if required.

Diuretics: The natriuretic effect of furosemide has been reported to be inhibited by some drugs of this class.

Lithium: Inhibition of renal lithium clearance leading to increases in plasma lithium concentrations have also been reported.

Antihypertensive Drugs: Naproxen and other NSAIDs can reduce the antihypertensive effect of propranolol and other beta blockers as well as other antihypertensive agents.

Antacids: The rate of absorption of naproxen is altered by concomitant administration of antacids but is not adversely influenced by the presence of food.

Probenecid: Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.

Cholestyramine: Concomitant administration of cholestyramine can delay the absorption of naproxen, but does not affect its extent.

Methotrexate: Caution is advised in the concomitant administration of naproxen and methotrexate since naproxen and other NSAIDs have been reported to reduce the tubular secretion of methotrexate in an animal model, thereby possibly enhancing its toxicity.

Glucocorticoids: Numerous studies have shown that the concomitant use of NSAIDs and oral glucocorticoids increases the risk of gastrointestinal side effects such as ulceration and bleeding. This is especially the case in older (>65 years of age) individuals.

Acetaminophen: Prolonged concurrent use of acetaminophen with an NSAID may increase the risk of adverse renal effects. Therefore it is recommended that patients be under close medical supervision while receiving such combined therapy.

Alcohol/Potassium Supplements: Concurrent use of alcohol or potassium supplements with an NSAID may increase the risk of gastrointestinal side effects including ulceration and hemorrhage.

Cyclosporine: Inhibition of renal prostaglandin activity by NSAIDs may increase the plasma concentration of cyclosporine and/or the risk of cyclosporine induced nephrotoxicity. Patients should be carefully monitored during concurrent use.

Digoxin: Concomitant administration of an NSAID with digoxin can result in an increase in digoxin concentrations which may result in digitalis toxicity. Increased monitoring and dosage adjustments of digitalis glycosides may be necessary during and following concurrent NSAID therapy.

Naproxen decreases platelet aggregation and prolongs bleeding time. This effect should be kept in mind when bleeding times are determined. Other laboratory tests in patients on naproxen therapy have shown sporadic abnormalities but no definite trend was seen that would indicate potential toxicity.

The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-dinitrobenzene used in this assay. Although 17-hydroxy corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that Naprosyn therapy be temporarily discontinued 48 hours before adrenal function tests are performed.

The drug may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).