Naproxen is indicated for:

• The treatment of osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis.
• 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., APO-NAPROXEN EC and APO-NAPROXEN SR) are not recommended for initial treatment of acute pain because the absorption of Naproxen is delayed.

For patients with an increased risk of developing cardiovascular and/or gastrointestinal adverse events, other management strategies that do NOT include the use of NSAIDs should be considered first. (See CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS).

Use of Naproxen should be limited to the lowest effective dose for the shortest possible duration of treatment in order to minimize the potential risk for cardiovascular or gastrointestinal adverse events. (See CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS)

Naproxen, as a NSAID, does NOT treat clinical disease or prevent its progression.

Naproxen, as a NSAID, only relieves symptoms and decreases inflammation for as long as the patient continues to take it.

Geriatrics (> 65 years of age):

Evidence from clinical studies and postmarket experience suggests that use in the geriatric population is associated with differences in safety (see WARNINGS AND PRECAUTIONS).

Pediatrics (< 2 years of age):

Naproxen should not be used in children under 2 years of age. The safety and efficacy in infants younger than 2 years of age has not been established.

APO-NAPROXEN EC and APO-NAPROXEN SR have not been studied in subjects under the age of 18.

Adult

Osteoarthritis / Rheumatoid Arthritis / Ankylosing Spondylitis

Oral: The usual total daily dosage for osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis is 500 mg a day in divided doses.  It may be increased gradually to 750 or 1000 mg, or decreased, depending on the response of the patient.

Studies have not shown any clinically significant benefit in using doses higher than 1000 mg/day.  In patients who tolerate lower doses of naproxen well and who exhibit only a partial response to 100 mg/day, the dose may be increased to 1500 mg/day for limited periods.

Experience with 1500 mg/day naproxen is limited to using the standard tablets.  Naproxen (naproxen) tablets should be swallowed with food or milk.

When treating such patients with naproxen 1500 mg/day, the physician should observe sufficient increased clinical benefit to offset the potential increased risk (see Undesirable effects).

In addition, patients on 1500 mg/day need to be followed closely for the development of any adverse events.

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

Patients with rheumatoid arthritis or osteoarthritis maintained on a dose of 750 mg/day in divided doses can be switched to a once daily dose of APO-NAPROXEN SR (naproxen sustained- release) 750 mg.  The single daily dose of APO-NAPROXEN SR should not be exceeded and can be administered in the morning or evening. APO-NAPROXEN SR tablets should be swallowed whole.

Naproxen sustained-release tablets and naproxen enteric-coated tablets have not been studied in subjects under the age of 18.

Analgesia / Musculoskeletal Injuries

Oral: The recommended dose is 750 mg/day divided into either two or three doses/day. This may be increased to 1000 mg/day if needed. The lowest effective dose should be used.

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.

Dysmenorrhea

Oral: The recommended starting dose is two 250 mg tablets, followed by one 250 mg tablet every 6 – 8 hours, as required. The total daily dose should not exceed 5 tablets (1250 mg). Alternatively, one 500 mg tablet given twice daily may be used.

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.

Missed Dose

The missed dose should be taken as soon as remembered, and then the regular dosing schedule should be continued. Two doses of Naproxen should not be taken at the same time.

GENERAL

Frail or debilitated patients may tolerate side effects less well and therefore special care should be taken in treating this population. To minimize the potential risk for an adverse event, the lowest effective dose should be used for the shortest possible duration. As with other NSAIDs, caution should be used in the treatment of elderly patients who are more likely to be suffering from impaired renal, hepatic or cardiac function. For high risk patients, alternate therapies that do not involve NSAIDs should be considered.

Naproxen is NOT recommended for use with other NSAIDs, with the exception of low-dose ASA for cardiovascular prophylaxis, because of the absence of any evidence demonstrating synergistic benefits and the potential for additive adverse reactions. (See DRUG INTERACTIONS: Drug-Drug Interactions, Acetylsalicylic acid (ASA) or other NSAIDs)

Naproxen should not be used concomitantly with the related drug APO-NAPRO-NA (naproxen sodium) since they both circulate in plasma as the naproxen anion.

Carcinogenesis and Mutagenesis

There is no evidence from animal data that Naproxen is carcinogenic or mutagenic (see Part II, TOXICOLOGY, for animal studies).

Cardiovascular and Cerebrovascular Events

Naproxen is a non-steroidal anti-inflammatory drug (NSAID). Use of some NSAIDs is associated with an increased incidence of cardiovascular adverse events (such as myocardial infarction, stroke or thrombotic events) which can be fatal. The risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk.

Caution should be exercised in prescribing  Naproxen to patients with risk factors for cardiovascular disease, cerebrovascular disease or renal disease, such as any of the following (NOT an exhaustive list):

• Hypertension
• Dyslipidemia / Hyperlipidemia
• Diabetes Mellitus
• Congestive Heart Failure (NYHA I)
• Coronary Artery Disease (Atherosclerosis)
• Peripheral Arterial Disease
• Smoking
• Creatinine Clearance < 60 mL/min or 1 mL/sec

Use of NSAIDs, such as Naproxen, can lead to new hypertension or can worsen pre-existing hypertension, either of which may increase the risk of cardiovascular events as described above. Thus blood pressure should be monitored regularly. Consideration should be given to discontinuing Naproxen should hypertension either develop or worsen with its use.

Use of NSAIDs, such as Naproxen, can induce fluid retention and edema, and may exacerbate congestive heart failure, through a renally-mediated mechanism. (See WARNINGS AND PRECAUTIONS: Renal, Fluid and Electrolyte Balance).

For patients with a high risk of developing an adverse CV event, other management strategies that do NOT include the use of NSAIDs should be considered first. To minimize the potential risk for an adverse CV event, the lowest effective dose should be used for the shortest possible duration.

Endocrine and Metabolism

Corticosteroids: Naproxen is NOT a substitute for corticosteroids. It does NOT treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to exacerbation of corticosteroid-responsive illness. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids. (see DRUG INTERACTIONS: Drug-Drug Interactions, Glucocorticoids)

Gastrointestinal

Serious GI toxicity, such as peptic ulceration, inflammation gastrointestinal bleeding, sometimes severe and occasionally fatal can occur at any time, with or without warning symptoms in patients treated with non-steroidal anti-inflammatory drugs (NSAIDs) including Naproxen (naproxen).

Minor upper GI problems, such as dyspepsia, are common, usually developing early in therapy. Health care providers should remain alert for ulceration and bleeding in patients treated with Naproxen, even in the absence of previous GI tract symptoms. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore special care should be taken in treating this population. To minimize the potential risk for an adverse GI event, the lowest effective dose should be used for the shortest possible duration. For high risk patients, alternate therapies that do not involve NSAIDs should be considered. (see WARNINGS AND PRECAUTIONS: Special Populations, Geriatrics)

Physicians should inform patients about the signs and/or symptoms of serious GI toxicity and instruct them to contact a physician immediately if they experience any such symptoms. The utility of periodic laboratory monitoring has NOT been demonstrated, nor has it been adequately assessed. Most patients who develop a serious upper GI adverse event on NSAID therapy have no symptoms. Upper GI ulcers, gross bleeding or perforation, caused by NSAIDs, appear to occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. These trends continue, thus increasing the likelihood of developing a serious GI event at some time during the course of therapy. Even short-term therapy has its risks.

Caution should be taken if prescribing Naproxen to patients with a prior history of peptic / duodenal ulcer disease or gastrointestinal bleeding as these individuals have a greater than 10- fold higher risk for developing a GI bleed when taking a NSAID than patients with neither of these risk factors. Other risk factors for GI ulceration and bleeding include the following: Helicobacter pylori infection, increased age, prolonged use of NSAID therapy, excess alcohol intake, smoking, poor general health status or concomitant therapy with any of the following:

• Anti-coagulants (e.g. warfarin)
• Anti-platelet agents (e.g. ASA, clopidogrel)
• Oral corticosteroids (e.g. prednisone)
• Selective Serotonin Reuptake Inhibitors (SSRIs) (e.g. citalopram, fluoxetine, paroxetine, sertraline)

Genitourinary

Some NSAIDs are associated with 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 a NSAID. Should urinary symptoms occur, in the absence of an alternate explanation, treatment with Naproxen should be stopped to ascertain if symptoms disappear. This should be done before urological investigations or treatments are carried out.

Hematologic

NSAIDs inhibiting prostaglandin biosynthesis interfere with platelet function to varying degrees; patients who may be adversely affected by such an action, such as those on anti-coagulants or suffering from haemophilia or platelet disorders should be carefully observed when Naproxen is administered.

Anti-coagulants: Numerous studies have shown that the concomitant use of NSAIDs and anticoagulants increases the risk of bleeding. Concurrent therapy of Naproxen with warfarin requires close monitoring of the international normalized ratio (INR).

Even with therapeutic INR monitoring, increased bleeding may occur.

Anti-platelet Effects: NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike acetylsalicylic acid (ASA), their effect on platelet function is quantitatively less, or of shorter duration, and is reversible.

Naproxen and other NSAIDs have no proven efficacy as anti-platelet agents and should NOT be used as a substitute for ASA or other anti-platelet agents for prophylaxis of cardiovascular thromboembolic diseases. Anti-platelet therapies (e.g. ASA) should NOT be discontinued. There is some evidence that use of NSAIDs with ASA can markedly attenuate the cardioprotective effects of ASA. (see DRUG INTERACTIONS: Drug-Drug Interactions, Acetylsalicylic Acid or other NSAIDs)

Concomitant administration of Naproxen with low dose ASA increases the risk of GI ulceration and associated complications.

Blood dyscrasias: Blood dyscrasias (such as neutropenia, leukopenia, thrombocytopenia, aplastic anemia and agranulocytosis) associated with the use of NSAIDs are rare, but could occur with severe consequences.

Anemia is sometimes seen in patients receiving NSAIDs, including Naproxen. This may be due to fluid retention, GI blood loss, or an incompletely described effect upon erythropoiesis.

Patients on long-term treatment with NSAIDs, including Naproxen, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia or blood loss.

Hepatic/Biliary/Pancreatic

As with other NSAIDs, borderline elevations of one or more liver enzyme tests (AST, ALT, alkaline phosphatase) may occur in up to 15% of patients. These abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy.

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.

A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver function test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with this drug. Severe hepatic reactions including jaundice and cases of fatal hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes, 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 (e.g. jaundice), or if systemic manifestations occur (e.g. eosinophilia, associated with rash, etc.), this drug should be discontinued.

If there is a need to prescribe this drug in the presence of impaired liver function, it must be done under strict observation.

Hypersensitivity Reactions:

Anaphylactoid Reactions: As with NSAIDs in general, anaphylactoid reactions have occurred in patients without known prior exposure to Naproxen. In post-marketing experience, rare cases of anaphylactic/ anaphylactoid reactions and angioedema have been reported in patients receiving Naproxen. Naproxen should NOT be given to patients with the ASA-triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking ASA or other NSAIDs (see CONTRAINDICATIONS).

ASA-Intolerance: Naproxen should NOT be given to patients with complete or partial syndrome of ASA-intolerance (rhinosinusitis, urticaria/angioedema, nasal polyps, asthma) in whom asthma, anaphylaxis, urticaria/angioedema, rhinitis or other allergic manifestations are precipitated by ASA or other NSAIDs. 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 reaction (see CONTRAINDICATIONS).

Cross-sensitivity: Patients sensitive to one NSAID may be sensitive to any of the other NSAIDs as well.

Serious skin reactions: (See WARNINGS AND PRECAUTIONS: Skin)

Immune

(See WARNINGS AND PRECAUTIONS: Infection, Aseptic Meningitis)

Infection

Naproxen, in common with other NSAIDs, may mask signs and symptoms of an underlying infectious disease.

Aseptic Meningitis: Rarely, 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 tissue diseases, etc.) seem to be pre-disposed. Therefore, in such patients, the health care provider must be vigilant to the development of this complication.

Neurologic

Some patients may experience drowsiness, dizziness, blurred vision, vertigo, tinnitus, hearing loss, insomnia or depression with the use of NSAIDs, such as Naproxen. If patients experience such adverse reaction(s), they should exercise caution in carrying out activities that require alertness.

Ophthalmologic

Blurred and/or diminished vision has been reported with the use of NSAIDs. If such symptoms develop, Naproxen should be discontinued and an ophthalmologic examination performed.

Ophthalmologic examination should be carried out at periodic intervals in any patient receiving Naproxen for an extended period of time.

Peri-Operative Considerations

(See CONTRAINDICATIONS: Coronary Artery Bypass Graft Surgery)

Psychiatric

(See WARNINGS AND PRECAUTIONS: Neurologic)

Renal

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, hematuria, low grade proteinuria and occasionally nephrotic syndrome.

Renal insufficiency due to NSAID use is seen in patients with pre-renal conditions leading to reduction in renal blood flow or blood volume. Under these circumstances, renal prostaglandins help maintain renal perfusion and glomerular filtration rate (GFR). In these patients, administration of a NSAID may cause a reduction in prostaglandin synthesis leading to impaired renal function. Patients at greatest risk of this reaction are those with pre-existing renal insufficiency (GFR < 60 mL/min or 1 mL/s), dehydrated patients, patients on salt restricted diets, those with congestive heart failure, cirrhosis, liver dysfunction, taking angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, cyclosporin, diuretics, and those who are elderly. Serious or life-threatening renal failure has been reported in patients with normal or impaired renal function after short term therapy with NSAIDs. Even patients at risk who demonstrate the ability to tolerate a NSAID under stable conditions may decompensate during periods of added stress (e.g. dehydration due to gastroenteritis). Discontinuation of NSAIDs is usually followed by recovery to the pre-treatment state.

Caution should be used when initiating treatment with NSAIDs, such as Naproxen, in patients with considerable dehydration. Such patients should be rehydrated prior to initiation of therapy. Caution is also recommended in patients with pre-existing kidney disease.

Advanced Renal Disease: (See CONTRAINDICATIONS)

Fluid and Electrolyte Balance: Use of NSAIDs, such as Naproxen, can promote sodium retention in a dose-dependent manner, which can lead to fluid retention and edema, and consequences of increased blood pressure and exacerbation of congestive heart failure. Thus, caution should be exercised in prescribing Naproxen in patients with a history of congestive heart failure, compromised cardiac function, hypertension, increased age or other conditions predisposing to fluid retention (see WARNINGS AND PRECAUTIONS: Cardiovascular). Use of NSAIDs, such as Naproxen, can increase the risk of hyperkalemia, especially in patients with diabetes mellitus, renal failure, increased age, or those receiving concomitant therapy with adrenergic blockers, angiotensin-converting enzyme inhibitors, angiotensin-II receptor antagonists, cyclosporin, or some diuretics.

Electrolytes should be monitored periodically (see CONTRAINDICATIONS).

Respiratory

ASA-induced asthma is an uncommon but very important indication of ASA and NSAID sensitivity. It occurs more frequently in patients with asthma who have nasal polyps.

Sexual Function/Reproduction

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. Therefore, in women who have difficulties conceiving, or who are undergoing investigation of infertility, withdrawal of Naproxen should be considered.

Skin

In rare cases, serious skin reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative dermatitis and erythema multiforme have been associated with the use of some NSAIDs. Because the rate of these reactions is low, they have usually been noted during post-marketing surveillance in patients taking other medications also associated with the potential development of these serious skin reactions. Thus, causality is NOT clear. These reactions are potentially life threatening but may be reversible if the causative agent is discontinued and appropriate treatment instituted. Patients should be advised that if they experience a skin rash they should discontinue their NSAID and contact their physician for assessment and advice, including which additional therapies to discontinue.

Special Populations

Pregnant Women: Naproxen is CONTRAINDICATED for use during the third trimester of pregnancy because of risk of premature closure of the ductus arteriosus and the potential to prolong parturition (see TOXICOLOGY).

Caution should be exercised in prescribing Naproxen during the first and second trimesters of pregnancy (see TOXICOLOGY).

Inhibition of prostaglandin synthesis may adversely affect pregnancy and/or the embryo-foetal development. Data from epidemiological studies suggest an increased risk of miscarriage and of cardiac malformation after use of a prostaglandin synthesis inhibitor in early pregnancy.

In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in increased pre- and post-implantation loss and embryo-foetal lethality. In addition, increased incidences of various malformations, including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period.

Naproxen is not recommended in labour and delivery because, through their prostaglandin synthesis inhibitory effect, they may adversely affect fetal circulation and inhibit uterine contractions, thus increasing the risk of uterine hemorrhage.

Nursing Women: (See CONTRAINDICATIONS)

Pediatrics: (See CONTRAINDICATIONS)

Geriatrics: Patients older than 65 years and frail or debilitated patients are more susceptible to a variety of adverse reactions from non-steroidal anti-inflammatory drugs (NSAIDs): the incidence of these adverse reactions increases with dose and duration of treatment.  In addition, these patients are less tolerant to ulceration and bleeding.  Most reports of fatal GI 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.

Monitoring and Laboratory Tests

Patients on long-term treatment with Naproxen should have their blood pressure monitored regularly and an ophthalmic examination should be carried out at periodic intervals (See WARNINGS AND PRECAUTIONS: Cardiovascular and Ophthalmic).

Hemoglobin, hematocrit, red blood cells (RBCs), white blood cells (WBCs), and platelets should be checked in patients on long-term treatment with Naproxen. Additionally, concurrent therapy with warfarin requires close monitoring of the international normalized ratio (INR) (See WARNINGS AND PRECAUTIONS: Hematology).

Serum transaminase and bilirubin should be monitored regularly during Naproxen therapy (see WARNINGS AND PRECAUTIONS: Hepatic, Biliary, Pancreatic).

Serum creatinine, creatine clearance and serum urea should be checked in patient during Naproxen therapy. Electrolytes including serum potassium should be monitored periodically (see WARNINGS AND PRECAUTIONS: Renal).

Monitoring of plasma lithium concentration is recommended when stopping or starting Naproxen therapy.

Acetylsalicylic acid (ASA) or other NSAIDs: The use of Naproxen (naproxen) in addition to any other NSAID, including those over the counter ones (such as ASA and ibuprofen) is NOT recommended because of the absence of any evidence demonstrating synergistic benefits and the possibility of additive adverse reactions.

The exception is the use of low dose ASA for cardiovascular protection, when another NSAID is being used for its analgesic/anti-inflammatory effect, keeping in mind that combination NSAID therapy is associated with additive adverse reactions.

Some NSAIDs (e.g. ibuprofen) may interfere with the anti-platelet effects of low dose ASA, possibly by competing with ASA for access to the active site of cyclooxygenase-1.

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 to therapy 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 adjustments of dose if required.

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

Antic-coagulants: (See WARNINGS AND PRECAUTIONS: Hematologic, Anticoagulants)

Anti-hypertensives: NSAIDs may diminish the anti-hypertensive effect of angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs).

Concomitant use of NSAIDs with ACE inhibitors or angiotensin receptor blockers may increase the risk of renal dysfunction, especially in patients with pre-existing poor renal function (see WARNINGS AND PRECAUTIONS: Renal).

Combinations of ACE inhibitors, angiotensin-II antagonists, or diuretics with NSAIDs might have an increased risk for acute renal failure and hyperkalemia. Blood pressure and renal function (including electrolytes) should be monitored more closely in this situation, as occasionally there can be a substantial increase in blood pressure.

Naproxen and other non-steroidal anti-inflammatory drugs can reduce the antihypertensive effect of propranolol and other beta-blockers as well as other antihypertensive agents.

Anti-platelet Agents (including ASA): There is an increased risk of bleeding, via inhibition of platelet function, when anti-platelet agents are combined with NSAIDs, such as Naproxen.(see WARNINGS AND PRECAUTIONS: Hematologic, Anti-platelet Effects)

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

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

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

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

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

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

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

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

Selective Serotonin Reuptake Inhibitors (SSRIs): Concomitant administration of NSAIDs and SSRIs may increase the risk of gastrointestinal ulceration and bleeding (see WARNINGS AND PRECAUTIONS: Gastrointestinal).

Drug-Food Interactions

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

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

Interactions with laboratory tests have not been established.

Drug-Lifestyle Interactions

There are no specific studies about effects on the ability to drive vehicles and to use machinery. Patients who experience visual disturbances or other central nervous system disturbances should refrain from these activities.

Concurrent use of alcohol with an NSAID may increase the risk of gastrointestinal side effects, including ulceration and hemorrhage.

Effects on Fertility

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.

Therefore, in women who have difficulties conceiving, or who are undergoing investigation of infertility, withdrawal of Naproxen should be considered.

Use in Pregnancy (Category C)

It is contraindicated in the third trimester of pregnancy, because of risk of premature closure of the ductus arteriosus and prolonged parturition women who are breastfeeding, because of the potential for serious adverse reactions in nursing infants.

Use in Lactation

Daily oral administration of 15, 30 or 60 mg/kg of naproxen to female rabbits from 2 weeks before mating until day 20 of pregnancy did not affect fertility, gestation, or the numbers of live fetuses.

In a peri- and post-natal study in rats, oral doses of naproxen up to 20 mg/kg administered daily during the last part of pregnancy through weaning did not result in adverse effects in viability of pups, lactation index, sex ratio, or weight gain of offspring. However, there was a slight increase in gestation length at the 10 and 20 mg/kg dose levels; and at the 10 mg/kg dose level, there was a significant increase in stillbirths.

Naproxen at daily oral doses of 12, 36 or 108 mg/kg to female mice from 2 weeks before mating until weaning of the pups did not cause changes in length of gestation, number of pups born, average pup weight at 0, 4, 7, 14 or 21 days, or sex distribution. The fertility index, gestation index, and 4-day viability index were similar for mice from the control and treated groups.  The 21-day survival and lactation indexes were decreased for mice from the group fed 108 mg/kg/day of naproxen, but not for mice given 12 or 36 mg/kg/day. Most of this change was due to maternal mortality in the high dose group.

Recent evidence suggests that inhibition of prostaglandin synthesis by non-steroidal anti- inflammatory compounds may be related to decreased uterine contractibility.  Thus, the onset of labor in a rat model system can be delayed with naproxen administration without causing maternal or fetal deaths in excess of that seen in controls. Since it has been shown that naproxen inhibits prostaglandin synthesis in vitro, it has been suggested that the effects of naproxen on uterine contractility are mediated through that mechanism.

Maternal and fetal deaths seen in naproxen-treated rats were, therefore, apparently related to dystocia rather than to a direct toxic effect of the compound. Naproxen is not unique in this regard, since comparable results were obtained in the rat with other commonly used non- steroidal anti-inflammatory agents.

There are no specific studies about effects on the ability to drive vehicles and to use machinery.

Patients who experience visual disturbances or other central nervous system disturbances should refrain from these activities.

Adverse Drug Reaction Overview

The most common adverse reactions encountered with nonsteroidal anti-inflammatory drugs are gastrointestinal, of which peptic ulcer, with or without bleeding, is the most severe. Fatalities have occurred particularly in the elderly.

As with all drugs in this class, the frequency and severity of adverse events depends on several factors: the dose of the drug and duration of treatment; the age, the sex, physical condition of the patient; any concurrent medical diagnoses or individual risk factors.

Clinical Trial Adverse Drug Reactions

A clinical study found gastrointestinal reactions to be more frequent and more severe in rheumatoid arthritis patients taking daily doses of 1500 mg naproxen compared to those taking 750 mg naproxen.

The adverse reactions in controlled clinical trials in 960 patients with rheumatoid arthritis or osteoarthritis treated with the Naproxen standard tablets are listed below.

Post-Market Adverse Drug Reactions

The following additional adverse events have been reported with NSAIDs including naproxen and naproxen sodium:

Gastrointestinal: Inflammation, bleeding (sometimes fatal, particularly in the elderly), ulceration, perforation and obstruction of the upper or lower gastrointestinal tract. Oesophagitis, gastritis, pancreatitis, stomatitis. Exacerbation of ulcerative colitis and Crohn’s disease. Heartburn, dyspepsia, abdominal pain, nausea, vomiting, diarrhoea, flatulence, constipation, haematemesis, melaena.

Infections: aseptic meningitis

Blood and Lymphatic System Disorders: agranulocytosis, aplastic anaemia, eosinophilia, haemolytic anaemia, leucopoenia, thrombocytopenia

Immune System Disorders : anaphylactoid reactions

Metabolic and Nutrition Disorders: hyperkalemia

Psychiatric Disorders: depression, dream abnormalities, insomnia

Nervous System: dizziness, drowsiness, headache, lightheadedness, retrobulbar optic neuritis convulsions, cognitive dysfunction, inability to concentrate

Eye Disorders: visual disturbances, corneal opacity, papillitis, papilloedema

Ear and Labyrinth Disorders: hearing impairment, hearing disturbances, tinnitus, vertigo

Cardiac Disorders:  palpitations, cardiac failure has been reported in association with NSAID treatment, congestive heart failure

Vascular Disorders: Clinical trial and epidemiological data suggest that use of coxibs and some NSAIDs (particularly at high doses and in long term treatment) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke)

Respiratory, Thoracic and Mediastinal Disorders: dyspnoea, pulmonary oedema, asthma, eosinophilic pneumonitis.

Hepatobiliary Disorders: hepatitis (some cases of hepatitis have been fatal), jaundice.

Skin and Subcutaneous Tissue Disorders:  ecchymoses, itching (pruritus), purpura, skin eruptions, sweating,alopecia, epidermal necrolysis, very rarely toxic epidermal necrolysis, erythema multiforme, bullous reactions, including Stevens-Johnson syndrome, erythema nodosum, fixed drug eruption, lichen planus, pustular reaction, skin rashes, SLE, urticaria, photosensitivity reactions, including rare cases resembling porphyria cutanea tarda (“pseudoporphyria”) or epidermolysis bullosa and angioneurotic oedema.

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

Musculoskeletal and Connective Tissue Disorders: myalgia, muscle weakness.

Renal and Urinary Disorders: haematuria, interstitial nephritis, nephrotic syndrome, renal disease, renal failure, renal papillary necrosis

Reproductive System and Breast Disorders:  female infertility

General Disorders and Administration Site Conditions: oedema, thirst, pyrexia (chills and fever), malaise

Investigations: abnormal liver function tests, raised serum creatinine

Symptoms and Signs

Significant overdosage may be characterized by drowsiness, dizziness, disorientation, heartburn, indigestion, epigastric pain, abdominal discomfort, nausea, vomiting, transient alterations in liver function, hypoprothrombinemia, renal dysfunction, metabolic acidosis and apnea.  A few patients have experienced convulsions, but it is not clear whether or not these were naproxen related.

Gastrointestinal bleeding may occur. Hypertension, acute renal failure, respiratory depression and coma may occur after the ingestion of NSAIDs but are rare.

Anaphylactoid reactions have been repeated with therapeutic ingestion of NSAIDs, and may occur following an overdose.

Treatment

Patients should be managed by symptomatic and supportive care following NSAIDs overdose. There are no specific antidotes. Prevention of further absorption (e.g. activated charcoal) may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large overdose. Forced diuresis, alkalinization of urine, haemodialysis, or haemoperfusion may not be useful due to high protein binding.

Mechanism of Action

Naproxen contains naproxen, a member of the arylacetic acid group of NSAIDs.

Naproxen is a nonsteroidal anti-inflammatory drug (NSAID) with analgesic properties. The mechanism of action of naproxen, like that of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition. During clinical trials, naproxen has been found to be less likely to cause gastrointestinal bleeding in doses usually used than is acetylsalicylic acid.

Naproxen has been shown to possess marked anti-inflammatory, analgesic and antipyretic activity, as assessed by a variety of animal test procedures.

Anti-inflammatory activity: In the rat paw edema assay, naproxen was more potent than phenylbutazone and acetylsalicylic acid and slightly less potent than indomethacin.

In the rat granuloma assay, naproxen was more active than phenylbutazone, and less active than indomethacin.

Analgesic activity: In a mouse analgesic assay using phenylquinone for pain induction, naproxen was more active than phenylbutazone and acetylsalicylic acid, and less active than indomethacin.  Parallel comparative analgesic studies were done in rats with yeast-induced paw edema.

In these assays, naproxen had a higher relative potency than phenylbutazone and acetylsalicylic acid, but lower relative potency when compared to indomethacin.

The comparative absorption, distribution, metabolism, and excretion of naproxen were studied in several species, including man. Naproxen was found to be rapidly absorbed in all species and, once in the blood, was eliminated with half-lives ranging from 2 to 35 hours.  Estimated volumes of distribution indicated that a large fraction of the drug is held in the blood, much like salicylates are.  Virtually all of the drug present in the blood of humans was determined to be unchanged naproxen, while the rat and monkey showed minor amounts of transformation products.  With the exception of the dog, all species excreted naproxen and its metabolic transformation products predominantly in the urine.  In the dog, the preferred route was fecal.

Studies by Tomlinson et al, have shown that naproxen can inhibit the synthesis of prostaglandin E2 from arachidonic acid by bovine seminal vesical microsomes. Naproxen therefore appears to act, at least in part, in a manner similar to other anti-inflammatory agents which block prostaglandin biosynthesis.

Human metabolic studies:

The plasma-level response to oral naproxen doses ranging up to 900 mg twice daily was studied in normal subjects.  Experiments with tritium-labelled naproxen showed that there was no difference in the fraction of ingested drug excreted in the stools whether the dose was 250 mg or 900 mg, thus eliminating the possibility that this effect was a result of incomplete absorption.

Accelerated renal clearance at high doses because of disproportionate increases in the amount of unbound drug appeared to be the most likely explanation for the plateau effect.

In patients treated with maintenance dialysis for terminal renal failure, serum level studies indicated that the metabolite 6-0-desmethyl naproxen is dialysed, whilst naproxen is not.  No accumulation of naproxen was found although serum levels of the metabolite increased.

Naproxen is rapidly and completely absorbed from the gastrointestinal tract. After administration of naproxen, peak plasma levels of naproxen anion are attained in 2 to 4 hours, with steady-state conditions normally achieved after 4-5 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 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. When naproxen is administered in the sustained-release form, 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 the sustained-release form of naproxen 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 the 750 and 1000 mg sustained-release naproxen tablets respectively, resulting in smaller fluctuations in plasma concentrations of naproxen with the sustained-release naproxen tablets.

The average Tmax 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 post-prandial; 9.7 hours fasting). The average Cmax increased significantly from 63.1

mg/mL (fasting) to 86.1 mg/mL (post-prandial).  This increase in Cmax was still lower than that observed with the 1000 mg dose of standard naproxen tablets. Based upon the 95% confidence interval, the AUCs were equivalent when the SR tablet was administered under fasting and non- fasting conditions.

A 28 day study of chromium 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. Enteric-coated naproxen is 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 mg and 500 mg tablets, except for a substantially increased time to peak plasma concentration (Tmax). The average maximum plasma concentration (Cmax) following the 375 mg, 2 x 250 mg and 500 mg enteric-coated tablets were 47.9, 58.2 and 60.7 µg/mL, while the Cmax following the 375 mg and 500 mg standard immediate release tablets were 46.6 and 63.1 µg/mL respectively. The Tmax’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) enteric-coated naproxen and standard naproxen were equivalent to each other with respect to Cmax, Cave, Cmax/Cave, 0-12 hours AUC and half-life.  In addition, fluctuations in plasma levels about Cave were considerably less with naproxen enteric-coated tablets as compared to 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 Cmax (70.7 vs. 58.5 µg/mL) and earlier Tmax (5.2 vs. 8.7 hours) in comparison to the fasting condition.  Relative to the fasting state, the average Tmax was delayed following a high fat meal (5.6 – 8.7 hours fasting, 9.2 – 10.8 hours post prandial) while the average Cmax and AUC were bioequivalent.

Acute Animal Toxicity

The oral LD50 values for naproxen are as follows:

Hamsters:  4110 mg/kg

Rats: 543 mg/kg

Dogs: > 1000 mg/kg Mice: 1234 mg/kg

Subacute and Chronic Oral Toxicity

In subacute and chronic oral studies with naproxen in a variety of species, the principal pathologic effect was gastrointestinal irritation and ulceration. The lesions seen were predominantly in the small intestine and ranged from hyperemia to perforation and peritonitis. Nephropathy was seen occasionally in rats, mice, and rabbits at high-dose levels of naproxen, but not in rhesus monkeys or miniature pigs.  In the affected species, the pathologic changes occurred in the cortex and papilla. Some rats examined 14 days after single oral doses of 230 mg/kg or more of naproxen evidenced necrotic areas of cortical and papillary tissue.  Tubular dilation (ectasia) occurred in rabbits dosed orally for 14 days with 200 mg/kg/day or more of naproxen. An examination of unfixed renal tissue from rabbits so treated was conducted and revealed the presence of diffraction patterns similar to that of crystalline naproxen. This suggests that the ectasia observed was a physical response to deposition of excreted naproxen within the tubules.

In mice given oral doses of 120 mg/kg/day or more of naproxen for 6 months, the kidneys were characterized by a low, but non-dosage-related incidence of cortical sclerosis and papillary tip necrosis.  Chronic administration of high doses of naproxen to mice appears to be associated with exacerbation of spontaneous murine nephropathy.

A wide variation in susceptibility to gastrointestinal lesions from administration of naproxen was evident in the various species tested.  For example, 30 mg/kg/day was tolerated well by rats for 90 days, but the same dose was ulcerogenic when administered for 6 months. Rhesus monkeys and miniature swine exhibited no significant pathology when dosed with naproxen at 45 mg/kg/day for 30 days.  This dose of naproxen was also tolerated by miniature swine without obvious evidence of adverse effects when administered daily for one year.  In rhesus monkeys, doses as high as 120 mg/kg/day administered b.i.d. for 6 months produced no clinical or histopathological evidence of gastrointestinal irritation although occult blood in the feces occurred more frequently in these animals as compared to controls.  In rabbits, the maximum tolerated repeated oral dose is 200 mg/kg/day. Mice tolerated oral daily doses of 240 mg/kg/day for 6 months.  In both rabbits and mice, gastrointestinal and renal toxicity was reported at these dose levels.  In dogs, on the other hand, 5.0 mg/kg/day approaches the maximum tolerated dose. This peculiar canine susceptibility to gastrointestinal effects of non-steroidal anti-inflammatory agents has also been shown with indomethacin and ibuprofen.

In dogs, naproxen exhibits a considerably longer plasma half-life than it does in rats, guinea pigs, miniature swine, monkeys and man. The same observation has been made with ibuprofen in dogs compared to rats and man.  In addition, in the species listed, only the dog excretes significant amounts of administered naproxen in the feces (50%).  In the rat, guinea pigs, miniature swine, monkeys, and man, 86-94% of the administered drug is excreted in the urine.

The suggested enterohepatic circulation of naproxen in the dog (as judged by the fecal excretion) may be a major factor in the susceptibility of the dog to gastrointestinal irritation by this compound.

Pathologic changes in the spleen and mesenteric lymph nodes as well as peritoneal inflammation and adhesions were considered to be clearly secondary to the effects of high doses of naproxen on the gastrointestinal tract.  Moderate weight loss of the male secondary sex glands occurred in some studies in naproxen-treated rats and dogs. Histopathologically, the affected glands in some instances exhibited atrophic and/or hypoplastic changes characterized by decreased secretory material.  A possible estrogenic action of naproxen as a causative factor seems highly unlikely since in standard bioassay procedures, the drug exhibited no estrogenic activity.

Nevertheless, daily doses of naproxen as high as 30 mg/kg administered for 60 days before mating had no effect on fertility and reproductive performance of male rats. These results reflect the physiological integrity of the entire male reproductive apparatus after administration of naproxen throughout the spermatogenic cycle.

Effect on Induced Infections in Rabbits

To determine whether treatment with naproxen affects the ability of animals to respond to bacterial infection, rabbits were inoculated subcutaneously with Diplococcus pneumoniae.  For 21 days before bacterial challenge and during a 2-week post-challenge period the animals were dosed daily by gavage with 2, 10, or 20 mg/kg of naproxen. Clinical conditions, morbidity, mortality, gross and histopathologic changes were evaluated.  There were no apparent effects of naproxen in altering the response of the animals to bacterial challenge.

Teratology

In teratology studies, no skeletal or visceral anomalies or pathologic changes were induced in the fetuses of pregnant rats and rabbits treated during organogenesis with daily oral doses of naproxen up to 20 mg/kg.  In these studies, there were also no significant differences from controls in the number of live fetuses, resorptions, fetal weights or ano-genital distances.

Reproductive Studies

Daily oral administration of 15, 30 or 60 mg/kg of naproxen to female rabbits from 2 weeks before mating until day 20 of pregnancy did not affect fertility, gestation, or the numbers of live fetuses.

In a peri- and post-natal study in rats, oral doses of naproxen up to 20 mg/kg administered daily during the last part of pregnancy through weaning did not result in adverse effects in viability of pups, lactation index, sex ratio, or weight gain of offspring. However, there was a slight increase in gestation length at the 10 and 20 mg/kg dose levels; and at the 10 mg/kg dose level, there was a significant increase in stillbirths.

Naproxen at daily oral doses of 12, 36 or 108 mg/kg to female mice from 2 weeks before mating until weaning of the pups did not cause changes in length of gestation, number of pups born, average pup weight at 0, 4, 7, 14 or 21 days, or sex distribution. The fertility index, gestation index, and 4-day viability index were similar for mice from the control and treated groups.  The 21-day survival and lactation indexes were decreased for mice from the group fed 108 mg/kg/day of naproxen, but not for mice given 12 or 36 mg/kg/day. Most of this change was due to maternal mortality in the high dose group.

Recent evidence suggests that inhibition of prostaglandin synthesis by non-steroidal anti- inflammatory compounds may be related to decreased uterine contractibility.  Thus, the onset of labor in a rat model system can be delayed with naproxen administration without causing maternal or fetal deaths in excess of that seen in controls. Since it has been shown that naproxen inhibits prostaglandin synthesis in vitro, it has been suggested that the effects of naproxen on uterine contractility are mediated through that mechanism.

Maternal and fetal deaths seen in naproxen-treated rats were, therefore, apparently related to dystocia rather than to a direct toxic effect of the compound. Naproxen is not unique in this regard, since comparable results were obtained in the rat with other commonly used non- steroidal anti-inflammatory agents.

Carcinogenicity

Naproxen was administered with food to Sprague-Dawley rats for 24 months at doses of 8,16 and 24 mg/kg/day. naproxen was not carcinogenic in rats.

Mutagenicity

Mutagenicity was not seen in Salmonella typhimurium (5 cell lines), Sachharomyces cerevisisae

(1 cell line), and mouse lymphoma tests.

Not applicable.

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