NAPROXEN TABLETS, USP

Rev. 06/06

Rx Only

• NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk. (See WARNINGS).
• Naproxen is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).

• NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events. (See WARNINGS).

Naproxen is a member of the arylacetic acid group of nonsteroidal anti-inflammatory drugs.

The chemical name for naproxen is (S)-6-methoxy-α-methyl-2-naphthaleneacetic acid. Naproxen has the following structure:

Naproxen is an odorless, white to off-white crystalline substance. It is lipid-soluble, practically insoluble in water at low pH and freely soluble in water at high pH. The octanol/water partition coefficient of naproxen at pH 7.4 is 1.6 to 1.8.

Each tablet, for oral administration, contains 250 mg, 375 mg or 500 mg of naproxen. In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, magnesium stearate, povidone, and sodium starch glycolate.

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 less than proportional increase in plasma levels due to an increase in clearance caused by saturation of plasma protein binding at higher doses (average trough C_ss 36.5, 49.2 and 56.4 mg/L with 500, 1000 and 1500 mg daily doses of naproxen). The naproxen anion has been found in the milk of lactating women at a concentrations equivalent to approximately 1% of maximum naproxen concentration in plasma (see PRECAUTIONS: Nursing Mothers).

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

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%). The plasma half-life of the naproxen anion in humans ranges from 12 to 17 hours. The corresponding half-lives of both naproxen's metabolites and conjugates are shorter than 12 hours, and their rates of excretion have been found to coincide closely with the rate of naproxen disappearance from the plasma. In patients with renal failure metabolites may accumulate (see WARNINGS: Renal Effects).

Carefully consider the potential benefits and risks of naproxen and other treatment options before deciding to use naproxen tablets. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS).

Naproxen is indicated:

•  * For reduction of fever
•  * For relief of mild to moderate pain
•  * For relief of signs and symptoms of juvenile arthritis.
•  * For relief of the signs and symptoms of rheumatoid arthritis
•  * For relief of the signs and symptoms of osteoarthritis.
•  * For treatment of primary dysmenorrhea.
•  * For acute or long-term use in the relief of signs and symptoms of the following:
  • Ankylosing spondylitis
  • Acute painful shoulder (Acute subacromial bursitis/supraspinatus tendinitis)
  • Acute gouty arthritis

Naproxen tablets are also indicated

• For the relief of the signs and symptoms of tendinitis
• For the relief of the signs and symptoms of bursitis
• For the relief of the signs and symptoms of acute gout

Naproxen is contraindicated in patients with known hypersensitivity to prescription as well as to over-the-counter products containing naproxen.

Naproxen should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients (see WARNINGS - Anaphylactoid Reactions, and PRECAUTIONS - Preexisting Asthma).

Naproxen is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).

NSAIDs, including naproxen, can cause serious gastrointestinal (Gl) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper Gl adverse event on NSAID therapy, is symptomatic. Upper Gl ulcers, gross bleeding, or perforation caused by NSAIDs 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 with longer duration of use, increasing the likelihood of developing a serious Gl event at some time during the course of therapy. However, even short-term therapy is not without risk.

NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a Gl bleed compared to patients with neither of these risk factors. Other factors that increase the risk for Gl bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal Gl 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 Gl event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of Gl ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious Gl adverse event is suspected. This should include discontinuation of the NSAID until a serious Gl adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered.

Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a nonsteriodal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state (see WARNINGS: Advanced Renal Disease).

No information is available from controlled clinical studies regarding the use of naproxen in patients with advanced renal disease. Therefore, treatment with naproxen is not recommended in these patients with advanced renal disease. If naproxen therapy must be initiated, close monitoring of the patient's renal function is advisable.

As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to naproxen. Naproxen should not be given to patients with the aspirin 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 aspirin or other NSAIDs (see CONTRAINDICATIONS and PRECAUTIONS - Preexisting Asthma). Emergency help should be sought in cases where an anaphylactoid reaction occurs.

NSAIDs including naproxen, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.

In late pregnancy, as with other NSAIDs, naproxen should be avoided because it may cause premature closure of the ductus arteriosus.

Naproxen cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids and the patient should be observed closely for any evidence of adverse effects, including adrenal insufficiency and exacerbation of symptoms of arthritis. Patients with initial hemoglobin values of 10g or less who are to receive long-term therapy should have hemoglobin values determined periodically.

The pharmacological activity of naproxen in reducing [fever and] inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, noninflammatory painful conditions.

Because of adverse eye findings in animal studies with drugs of this class, it is recommended that ophthalmic studies be carried out if any change or disturbance in vision occurs.

Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including naproxen. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported.

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 a more severe hepatic reaction while on therapy with naproxen. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), naproxen should be discontinued. Chronic alcoholic liver disease and probably other diseases with decreased or abnormal plasma proteins (albumin) reduced the total plasma concentration of naproxen, but the plasma concentrations 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.

Anemia is sometimes seen in patients receiving NSAIDs, including naproxen. This may be due to fluid retention, occult or gross Gl 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.

NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving naproxen who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.

Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, naproxen should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.

Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.

• Naproxen, like other NSAIDs, may cause serious CV side effects, such as Ml or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS, Cardiovascular Effects).
• Naproxen, like other NSAIDs, can cause Gl discomfort and, rarely, serious Gl side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious Gl tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS, Gastrointestinal Effects: Risk of Ulceration, Bleeding, and Perforation).
• Naproxen, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and bulers, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible.
• Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians.
• Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy.
• Patients should be informed of the signs of an anaphylactoid reaction (e.g. difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS).
• In late pregnancy, as with other NSAIDs, naproxen should be avoided because it will cause premature closure of the ductus arteriosus.
• Caution should be exercised by patients whose activities require alertness if they experience drowsiness, dizziness, vertigo or depression during therapy with naproxen.

Because serious Gl tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of Gl bleeding. Patients on long-term treatment with NSAIDs, should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, naproxen should be discontinued.

Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin. Patients simultaneously receiving naproxen and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required.

Naproxen and other nonsteroidal anti-inflammatory drugs can reduce the antihypertensive effect of propranolol and other beta-blockers.

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

A 2-year study was performed in rats to evaluate the carcinogenic potential of naproxen at doses of 8, 16, and 24 mg/kg/day (50, 100, and 150 mg/m²). The maximum dose used was 0.28 times the systemic exposure to humans at the recommended dose. No evidence of tumorigenicity was found.

In rat studies with NSAID's as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. Naproxen-containing products are not recommended in labor and delivery because, through its prostaglandin synthesis inhibitory effects, naproxen may be adversely affect fetal circulation and inhibit uterine contractions, thus increasing the risk of uterine hemorrhage. The effects of naproxen on labor and delivery in pregnant women are unknown.

The naproxen anion has been found in the milk of lactating women at a concentration in plasma. Because of the possible adverse effects of prostaglandin-inhibiting drugs on neonates, use in nursing mothers should be avoided.

Safety and effectiveness in pediatric patients below the age of 2 years have not been established. Pediatric dosing recommendations for juvenile arthritis are based on well-controlled studies (see DOSAGE AND ADMINISTRATION). There are no adequate effectiveness or dose-response data for other pediatric conditions, but the experience in juvenile arthritis and other use experience have established that single doses of 2.5 to 5 mg/kg, with total daily dose not exceeding 15 mg/kg/day, are well tolerated in pediatric patients over 2 years of age.

Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly. Caution is advised when high doses are required and some adjustment of dosage may be required in elderly patients. As with other drugs used in the elderly, it is prudent to use the lowest effective dose.

Experience indicates that geriatric patients may be particularly sensitive to certain adverse effects of nonsteriodal antiinflammatory drugs. Elderly or debilitated patients seem to tolerate peptic ulceration or bleeding less well when these events do occur. Most spontaneous reports of fatal Gl events are in the geriatric population (see WARNINGS).

Naproxen is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Geriatric patients may be at a greater risk for the development of a form of renal toxicity precipitated by reduced prostaglandin formation during administration of nonsteroidal anti-inflammatory drugs (see WARNINGS: Renal Effects).

Adverse reactions reported in controlled clinical trials in 960 patients treated for rheumatoid arthritis or osteoarthritis are uled below. In general, reactions in patients treated chronically were reported 2 to 10 times more frequently than they were in short-term studies in the 962 patients treated for mild to moderate pain or for dysmenorrhea. The most frequent complaints reported related to the gastrointestinal tract.

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 (see CLINICAL PHARMACOLOGY). In controlled clinical trials with about 80 pediatric patients and in well-monitored, open-label studies with about 400 pediatric patients with juvenile arthritis treated with naproxen, the incidence of rash and prolonged bleeding times were increased, the incidence of gastrointestinal and central nervous system reactions were about the same, and the incidence of other reactions were lower in pediatric patients than in adults.

In patients taking naproxen in clinical trials, the most frequently reported adverse experiences in approximately 1 to 10% of patients are:

Gastrointestinal (Gl) Experiences, including: heartburn*, abdominal pain*, nausea*, constipation*, diarrhea, dyspepsia, stomatitis

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

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

Special Senses: tinnitus*, visual disturbances, hearing disturbances

Cardiovascular: edema*, palpitations

General: dyspnea*, thirst

*Incidence of reported reaction between 3% and 9%. Those reactions occurring in less than 3% of the patients are unmarked. In patients taking NSAIDs, the following adverse experiences have also been reported in approximately 1 to 10% of patients.

Gastrointestinal (Gl) Experiences, including: flatulence, gross bleeding/perforation, Gl ulcers (gastric/duodenal), vomiting

General: abnormal renal function, anemia, elevated liver enzymes, increased bleeding time, rashes

The following are additional adverse experiences reported in <1% of patients taking naproxen during clinical trials and through post-marketing reports. Those adverse reactions observed through post-marketing reports are italicized.

Body as a Whole:anaphylactoid reactions, angioneurotic edema, menstrual disorders, pyrexia (chills and fever)

Cardiovascular:congestive heart failure, vasculitis, hypertension, pulmonary edema

Gastrointestinal: gastrointestinal bleeding and/or perforation, hematemesis, jaundice, pancreatitis, vomiting, colitis, abnormal liver function tests, nonpeptic gastrointestinal ulceration, ulcerative stomatitis

Hepatobiliary: jaundice, abnormal liver function tests, hepatitis (some cases have been fatal)

Hemic and Lymphatic:eosinophilia, leucopenia, melena, thrombocytopenia, agranulocytosis, granulocytopenia, hemolytic anemia, aplastic anemia

Metabolic and Nutritional:hyperglycemia, hypoglycemia

Nervous System: inability to concentrate, depression, dream abnormalities, insomnia, malaise, myalgia, muscle weakness, aseptic meningitis, cognitive dysfunction, convulsions

Respiratory:eosinophilic pneumonitis, asthma

Dermatologic:alopecia, urticaria, skin rashes, toxic epidermal necrolysis, erythema multiforme, erythema nodosum fixed drug eruption, lichen planus pustular reaction, systemic lupus erythematoses, Stevens-Johnson syndrome, photosensitive dermatitis, photosensitivity reactions, including rare cases resembling porphyria cutanea tarda (psuedoporphyria) or epidermolysis bullosa. If skin fragility, bulering or other symptoms suggestive of pseudoporphyria occur, treatment should be discontinued and the patient monitored.

Special Senses:hearing impairment, corneal opacity, papillitis, retrobulbar optic neuritis, papilledema

Urogenital:glomerular nephritis, hematuria, hyperkalemia, interstitial nephritis, nephrotic syndrome, renal disease, renal failure, renal papillary necrosis, raised serum creatinine

Reproduction (female):infertility

In patients taking NSAIDs, the following adverse experiences have also been reported in <1% of patients.

Body as a Whole: fever, infection, sepsis, anaphylactic reactions, appetite changes, death

Cardiovascular: hypertension, tachycardia, syncope, arrhythmia, hypotension, myocardial infarction

Gastrointestinal: dry mouth, esophagitis, gastric/peptic ulcers, gastritis, glossitis, hepatitis, eructation, liver failure

Hepatobiliary: hepatitis, liver failure

Hemic and Lymphatic: rectal bleeding, lymphadenopathy, pancytopenia

Metabolic and Nutritional: weight changes

Nervous System: anxiety, asthenia, confusion, nervousness, paresthesia, somnolence, tremors, convulsions, coma, hallucinations

Respiratory: asthma, respiratory depression, pneumonia

Dermatologic: exfoliative dermatitis

Special Senses: blurred vision, conjunctivitis

Urogenital: cystitis, dysuria, oliguria/polyuria, proteinuria

Significant naproxen overdosage may be characterized by lethargy, dizziness, drowsiness, epigastric pain, abdominal discomfort, heartburn, indigestion, nausea, transient alterations in liver function, hypoprothrombinemia, renal dysfunction, metabolic acidosis, apnea, disorientation or vomiting. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression, and coma may occur, but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an overdose. Because naproxen sodium may be rapidly absorbed, high and early blood levels should be anticipated. A few patients have experienced convulsions, but it is not clear whether or not these were drug-related. It is not known what dose of the drug would be life-threatening. The oral LD₅₀ of the drug is 543 mg/kg in rats, 1234 mg/kg in mice, 4110 mg/kg in hamsters, and greater than 1000 mg/kg in dogs.

Patients should be managed by symptomatic and supportive care following a NSAID overdose. There are no specific antidotes. Hemodialysis does not decrease the plasma concentration of naproxen because of the high degree of its protein binding. Emesis and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children) and/or osmotic cathartic may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large overdose. Forced diuresis, alkalinization of urine or hemoperfusion may not be useful due to high protein binding.

Carefully consider the potential benefits and risks of naproxen and other treatment options before deciding to use naproxen. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS).

After observing the response to initial therapy with naproxen, the dose and frequency should be adjusted to suit an individual patient's needs. Naproxen Tablets

•  250 mg      twice daily
•  or 375 mg    twice daily
•  or 500 mg    twice daily

Although naproxen circulates in the plasma they have pharmacokinetic differences that may affect onset of action. Onset of pain relief can begin within 30 minutes in patients taking naproxen sodium and within 1 hour in patients taking naproxen (see CLINICAL PHARMACOLOGY)

The recommended strategy for initiating therapy is to choose a formulation and a starting dose likely to be effective for the patient and then adjust the dosage based on observation of benefit and/or adverse events. A lower dose should be considered in patients with renal or hepatic impairment or in elderly patients (see WARNINGS and PRECAUTIONS).

Naproxen Tablets USP, 250 mg are white, round, unscored tablet; embossed "West-ward 346" and are available in:

•  Bottles of 30 tablets.
•  Bottles of 100 tablets.
•  Bottles of 500 tablets.

Naproxen Tablets USP, 375 mg are white, oblong, unscored tablet; embossed "West-ward 347" and are available in:

•  Bottles of 30 tablets.
•  Bottles of 100 tablets.
•  Bottles of 500 tablets.

Naproxen Tablets USP, 500 mg are white, oblong, unscored tablet; embossed "West-ward 348" and are available in:

•  Bottles of 30 tablets.
•  Bottles of 100 tablets.
•  Bottles of 500 tablets.

Store at controlled room temperature, 20-25°C (68-77°F) with excursions permitted between 15-30°C (59-86°). (See USP). Dispense in light-resistant containers.

Manufactured By:
West-ward Pharmaceutical Corp.
Eatontown, NJ 07724
Revised June 2006