NAPROXEN DELAYED-RELEASE TABLETS

naproxen (Naproxentablet, delayed release 
[ALPHAPHARM PTY. LTD. ]

Rx only

DESCRIPTION:

Naproxen is a member of the arylacetic acid group of nonsteroidal anti-inflammatory drugs. The chemical name for naproxen is (+)-6-Methoxy-α-methyl-2-naphthaleneacetic acid. Naproxen has the following structural formula.

Image from Drug Label Content

Molecular Formula: C14H14O3

Molecular Weight: 230.26

Naproxen is practically odourless, 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.

Naproxen delayed-release tablets are enteric-coated tablets containing 375 mg or 500 mg of naproxen and croscarmellose sodium, povidone and magnesium stearate. The enteric coating dispersion contains sodium hydroxide, methacrylic acid copolymer, talc, polyethylene glycol, titanium dioxide, simethicone emulsion and purified water. The dissolution of this enteric-coated naproxen tablet is pH dependent with rapid dissolution above pH 6. There is no dissolution below pH 4.

CLINICAL PHARMACOLOGY:

Naproxen is a nonsteroidal anti-flammatory drug with analgesic and antipyretic properties. The naproxen anion inhibits prostaglandin synthesis but beyond this its mode of action is unknown.

Pharmacokinetics:

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

Absorption

Delayed Release: Naproxen delayed-release tablets are designed with a pH-sensitive coating to provide a barrier to disintegration in the acidic environment of the stomach and to lose integrity in the more neutral environment of the small intestine. The enteric polymer coating selected for naproxen delayed-release tablets dissolves above pH 6. When naproxen delayed-release tablets were given to fasted subjects, peak plasma levels were attained about 4 to 6 hours following the first dose (range: 2 to 12 hours). An in vivo study in man using radiolabeled naproxen delayed-release tablets demonstrated that naproxen delayed-release tablets dissolve primarily in the small intestine rather than the stomach, so the absorption of the drug is delayed until the stomach is emptied.

When 500 mg of naproxen delayed-release tablets were given twice a day to fasted subjects (n=24), the following was observed after 1 week of dosing:

Cmax (mcg/mL) 94.9 (18%)*

Tmax (hours) 4 (39%)*

AUC0-12 hr (mcg•hr/mL) 845 (20%)*

* mean value (coefficient of variation)

Antacid Effects: When naproxen delayed-release tablets were given as a single dose with antacid (54 mEq buffering capacity) the peak plasma levels of naproxen were unchanged, but the time to peak was reduced (mean Tmax fasted 5.6 hours, mean Tmax with antacid 5 hours), although not significantly.

Food Effects: When naproxen delayed-release tablets were given as a single dose with food, peak plasma levels in most subjects were achieved in about 12 hours (range: 4 to 24 hours). Residence time in the small intestine until disintegration was independent of food intake. The presence of food prolonged the time the tablets remained in the stomach, time to first detectable serum naproxen levels, and time to maximal naproxen levels (Tmax), but did not affect peak naproxen levels (Cmax).

Distribution

Naproxen has a volume of distribution of 0.16 L/kg. At therapeutic levels naproxen is greater than 99% albumin-bound. As 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 Css 36.5, 49.2 and 56.4 mg/L with 500, 1000, and 1500 mg daily doses of naproxen). However, the concentration of unbound naproxen continues to increase proportionally to dose.

Metabolism

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

Elimination

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

Special Populations

Pediatric Patients: In pediatric patients aged 5 to 16 years with arthritis, plasma naproxen levels following a 5 mg/kg single dose of naproxen oral suspension were found to be similar to those found in normal adults following a 500 mg dose. The terminal half-life appears to be similar in pediatric and adult patients.

Pharmacokinetic studies of naproxen were not performed in pediatric patients younger than 5 years of age. Naproxen delayed-release tablets have not been studied in subjects under the age of 18.

Renal Insufficiency: Naproxen pharmacokinetics has not been determined in subjects with renal insufficiency. Given that naproxen, its metabolites, and conjugates are primarily excreted by the kidney, the potential exists for naproxen metabolites to accumulate in the presence of renal insufficiency.

CLINICAL STUDIES:

General Information:

Naproxen has been studied in patients with rheumatoid arthritis, osteoarthritis, juvenile arthritis and ankylosing spondylitis. Improvement in patients treated for rheumatoid arthritis was demonstrated by a reduction in joint swelling, a reduction induration of morning stiffness, a reduction in disease activity as assessed by both the investigator and patient, and by increased mobility as demonstrated by a reduction in walking time. Generally, response to naproxen has not been found to be dependent on age, sex, severity or duration of rheumatoid arthritis.

In patients with osteoarthritis, the therapeutic action of naproxen has been shown by a reduction in joint pain or tenderness, an increase in range of motion in knee joints, increased mobility as demonstrated by a reduction in walking time, and improvement in capacity to perform activities of daily living impaired by the disease.

In clinical studies in patients with rheumatoid arthritis, osteoarthritis and juvenile arthritis, naproxen has been shown to be comparable to aspirin and indomethacin in controlling the aforementioned measures of disease activity, but the frequency and severity of the milder gastrointestinal adverse effects(nausea, dyspepsia, heartburn) and nervous system adverse affects (tinnitus, dizziness, lightheadedness) were less in naproxen-treated patients than in those treated with aspirin or indomethacin.

In patients with ankylosing spondylitis, naproxen has been shown to decrease night pain, morning stiffness and pain at rest. In double-blind studies the drug was shown to be as effective as aspirin, but with fewer side effects.

Naproxen may be used safely in combination with gold salts and/or corticosteroids; however, in controlled clinical trials, when added to the regimen of patients receiving corticosteroids it did not appear to cause greater improvement over that seen with corticosteroids alone. Whether naproxen has a "steroid-sparing" effect has not been adequately studied. When added to the regimen of patients receiving gold salts, naproxen did result in greater improvement. Its use in combination with salicylates is not recommended because there is evidence that aspirin increases the rate of excretion of naproxen and data are inadequate to demonstrate that naproxen and aspirin produce greater improvement over that achieved with aspirin alone. In addition, as with other NSAIDs the combination may result in higher frequency of adverse events than demonstrated for either product alone.

Three 6-week, double-blind multicenter studies with naproxen delayed-release tablets (375 or 500 mg BID, n=385) and naproxen immediate-release tablets (375 or 500 mg BID, n=279) were conducted comparing naproxen delayed-release tablets with naproxen immediate-release tablets including 355 rheumatoid arthritis and osteoarthritis patients who had a recent history of NSAID related GI symptoms. These studies indicated that naproxen delayed-release tablets and naproxen immediate-release tablets showed no significant differences in efficacy or safety and had similar prevalence of minor GI complaints. Individual patients, however may find one formulation preferable to the other.

Five hundred and fifty-three patients received naproxen delayed-release tablets during long-term open label trials (mean length of treatment was 159 days). The rates for clinically-diagnosed peptic ulcers and GI bleeds were similar to what has been historically reported for long-term NSAID use.

INDIVIDUALIZATION OF DOSAGE:

Because naproxen delayed-release tablets dissolve in the small intestine rather than in the stomach, the absorption of the drug is delayed compared to other naproxen formulations (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 PRECAUTIONS).

Osteoarthritis/Rheumatoid Arthritis/Ankylosing Spondylitis:

The recommended dose of naproxen is naproxen delayed-release tablets 375 mg or 500 mg taken twice daily.

During long-term administration the dose of naproxen may be adjusted up or down depending on the clinical response of the patient. A lower daily dose may suffice for long-term administration. In patients who tolerate lower doses well, the dose may be increased to 1500 mg per day when a higher level of anti-inflammatory/analgesic activity is required. When treating patients with naproxen 1500 mg/day, the physician should observe sufficient increased clinical benefit to offset the potential increased risk. The morning and evening doses do not have to be equal in size and administration of the drug more frequently than twice daily does not generally make a difference in response (see CLINICAL PHARMACOLOGY).

Juvenile Arthritis:

The use of naproxen oral suspension allows for more flexible dose titration.

The recommended total daily dose is approximately 10 mg/kg given in 2 divided doses (i.e., 5 mg/kg given twice a day) (see DOSAGE AND ADMINISTRATION).

INDICATIONS AND USAGE:

Naproxen delayed-release tablets are indicated for the treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis and juvenile arthritis. Naproxen oral suspension is recommended for juvenile rheumatoid arthritis in order to obtain the maximum dosage flexibility based on the patient's weight.

Naproxen delayed-release tablets are not recommended for initial treatment of acute pain because the absorption of naproxen is delayed compared to absorption from other naproxen-containing products (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

CONTRAINDICATIONS:

All naproxen products are contraindicated inpatients who have had allergic reactions to prescription as well as to over-the-counter products containing naproxen. It is also contraindicated in patients in whom aspirin or other nonsteroidal anti-inflammatory/analgesic drugs induce the syndrome of asthma, rhinitis and nasal polyps. Both types of reactions have the potential of being fatal. Anaphylactoid reactions to naproxen, whether of the true allergic type or the pharmacologic idiosyncratic (e.g., aspirin hypersensitivity syndrome) type, usually but not always occur inpatients with a known history of such reactions. Therefore, careful questioning of patients for such things as asthma, nasal polyps, urticaria and hypotension associated with nonsteroidal anti-inflammatory drugs before starting therapy is important. In addition, if such symptoms occur during therapy, treatment should be discontinued.

WARNINGS:

Risk of GI Ulceration, Bleeding and Perforation with NSAID Therapy:

Serious gastrointestinal toxicity such as bleeding, ulceration and perforation, can occur at any time, with or without warning symptoms, in patients treated chronically with NSAID therapy. Although 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 chronically with NSAIDs even in the absence of previous GI tract symptoms. In patients observed in clinical trials of several months to 2 years' duration, symptomatic upper GI ulcers, gross bleeding or perforation appear to occur in approximately 1% of patients treated for 3 to 6 months, and in about 2% to 4% of patients treated for one year.

Physicians should inform patients about the signs and/or symptoms of serious GI toxicity and what steps to take if they occur.

Studies to date with naproxen have not identified any subset of patients not at risk of developing peptic ulceration and bleeding or any differences between naproxen products in their propensity to cause peptic ulceration and bleeding. Except for a prior history of serious GI events and other risk factors known to be associated with peptic ulcer disease, such as alcoholism, smoking, etc., no risk factors (e.g., age, sex) have been associated with increased risk. Elderly or debilitated patients seem to tolerate ulceration or bleeding less well than other individuals and most spontaneous reports of fatal GI events are in this population. Studies to date are inconclusive concerning the relative risk of various NSAIDs in causing such reactions. High doses of any NSAID probably carry a greater risk of these reactions, although controlled clinical trials showing this do not exist in most cases. In considering the use of relatively large doses (within the recommended dosage range), sufficient benefit should be anticipated to offset the potential increased risk of GI toxicity.

PRECAUTIONS:

General:

NAPROXEN DELAYED-RELEASE TABLETS SHOULD NOT BE USED CONCOMITANTLY WITH OTHER NAPROXEN CONTAINING PRODUCTS SINCE THEY ALL CIRCULATE IN THE PLASMA AS THE NAPROXEN ANION.

If the steroid dose is reduced or eliminated during therapy, the steroid dosage should be reduced slowly and the patients 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 10 grams or less who are to receive long-term therapy should have hemoglobin values determined periodically.

The antipyretic and anti-inflammatory activities of the drug may reduce fever and inflammation, thus diminishing their utility as diagnostic signs in detecting complications of presumed non-infectious, non-inflammatory 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.

Renal Effects:

As with other nonsteroidal anti-inflammatory drugs, long-term administration of naproxen to animals has resulted in renal papillary necrosis and other abnormal renal pathology. In humans, there have been reports of acute interstitial nephritis, hematuria, proteinuria and occasionally nephrotic syndrome associated with naproxen-containing products and other NSAIDs since they have been marketed.

A second form of renal toxicity has been seen in patients taking naproxen as well as other nonsteroidal anti-inflammatory drugs. In patients with prerenal conditions leading to a reduction in renal blood flow or blood volume, where the renal prostaglandins have a supportive role in the maintenance of renal perfusion, administration of a nonsteroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and 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 the elderly. 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 caution in patients with significantly impaired renal function, and the monitoring of serum creatinine and/or creatinine clearance is advised in these patients. Caution should be used if the drug is given to patients with creatinine clearance of less than 20 mL/minute because accumulation of naproxen metabolites has been seen in such patients.

Chronic alcoholic liver disease and probably other diseases with decreased or abnormal plasma proteins (albumin) reduce the total plasma concentration of naproxen, but the plasma concentration of unbound naproxen in 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.

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.

Hepatic Function:

As with other nonsteroidal anti-inflammatory drugs, borderline elevations of one or more liver tests may occur in up to 15% of patients. These abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy. The SGPT (ALT) test is probably the most sensitive indicator of liver dysfunction. Meaningful (3 times the upper limit of normal) elevations of SGPT or SGOT (AST) occurred in controlled clinical trials in less than 1% of patients. 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 naproxen. Severe hepatic reactions, including jaundice and cases of fatal hepatitis, have been reported with naproxen as with other nonsteroidal anti-inflammatory drugs. 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.), naproxen should be discontinued.

Fluid Retention and Edema:

Peripheral edema has been observed in some patients receiving naproxen.

Information for Patients:

Naproxen, like other drugs of this class, is not free of side effects. The side effects of naproxen can cause discomfort and, rarely, there are more serious side effects, such as gastrointestinal bleeding, which may result in hospitalisation and even fatal outcomes.

NSAIDs (Nonsteroidal Anti-Inflammatory Drugs) are often essential agents in the management of arthritis and have a major role in the treatment of pain, but they also may be commonly employed for conditions which are less serious.

Physicians may wish to discuss with their patients the potential risks (see WARNINGS, PRECAUTIONS and ADVERSE REACTIONS) and likely benefits of naproxen treatment particularly when it is used for less serious conditions where treatment without NSAIDs may represent an acceptable alternative to both the patient and physician.

Caution should be exercised by patients whose activities require alertness if they experience drowsiness, dizziness, vertigo or depression during therapy with naproxen.

Laboratory Tests:

Because serious GI tract ulceration and bleeding can occur without warning symptoms, physicians should follow patients chronically treated with naproxen for signs and symptoms of ulceration and bleeding and should inform them of the importance of this follow-up and what they should do if certain signs and symptoms do appear (see WARNINGS, Risk of GI Ulcerations, Bleeding and Perforation with NSAID Therapy).

Drug Interactions:

The use of NSAIDs in patients who are receiving ACE inhibitors may potentiate renal disease states (see PRECAUTIONS, Renal Effects).

In vitro studies have shown that naproxen anion, because of its affinity for protein, may displace from their binding sites other drugs which are also albumin-bound (see CLINICAL PHARMACOLOGY, Pharmacokinetics).

Theoretically, the naproxen anion itself could likewise be displaced. Short-term controlled studies failed to show that taking the drug significantly affects prothrombin times when administered to individuals on coumarin-type anticoagulants. Caution is advised nonetheless, since interactions have been seen with other nonsteroidal agents of this class. Similarly, patients receiving the drug and a hydantoin, sulfonamide or sulfonylurea should be observed for signs of toxicity to these drugs (see CLINICAL STUDIES, General Information).

Concomitant administration of naproxen and aspirin is not recommended because naproxen is displaced from its binding sites during the concomitant administration of aspirin, resulting in lower plasma concentrations and peak plasma levels.

The natriuretic effect of furosemide has been reported to be inhibited by some drugs of this class. Inhibition of renal lithium clearance leading to increases in plasma lithium concentrations has also been reported. Naproxen and other nonsteroidal anti-inflammatory drugs can reduce the antihypertensive effect of propranolol and other beta-blockers.

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

Caution should be used if naproxen is administered concomitantly with methotrexate. Naproxen and other nonsteroidal anti-inflammatory drugs have been reported to reduce the tubular secretion of methotrexate in an animal model, possibly increasing the toxicity of methotrexate. Due to the gastric pH elevating effects of H2-blockers, sucralfate and intensive antacid therapy, concomitant administration of naproxen delayed-release tablets is not recommended.

Drug/Laboratory Test Interactions:

Naproxen may decrease platelet aggregation and prolong bleeding time. This effect should be kept in mind when bleeding times are determined.

The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because on an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay. Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used.

Naproxen may interfere with some urinary assays of 5-hydroxyindoleaceticacid (5HIAA).

Carcinogenesis:

A 2-year study was performed in rats to evaluate the carcinogenic potential of naproxen at rat 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.

Pregnancy:

Teratogenic Effects:

Pregnancy Category B.

Reproduction studies have been performed in rats at 20 mg/kg/day (125 mg/m2/day, 0.23 times the human systemic exposure), rabbits at 20 mg/kg/day (220 mg/m2/day, 0.27 times the human systemic exposure), and mice at 170 mg/kg/day (510 mg/m2/day, 0.28 times the human systemic exposure) with no evidence of impaired fertility or harm to the fetus due to the drug. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, naproxen should not be used during pregnancy unless clearly needed.

Nonteratogenic Effects:

There is some evidence to suggest that when inhibitors of prostaglandin synthesis are used to delay preterm labor there is an increased risk of neonatal complications such as necrotizing enterocolitis, patent ductus arteriosus and intracranial hemorrhage. Naproxen treatment given in late pregnancy to delay parturition has been associated with persistent pulmonary hypertension, renal dysfunction and abnormal prostaglandin E levels in preterm infants. Because of the known effect of drugs of this class on the human fetal cardiovascular system (closure of ductus arteriosus), use during third trimester should be avoided.

Nursing Mothers:

The naproxen anion has been found in the milk of lactating women at a concentration of approximately 1% of that found in plasma. Because of the possible adverse effects of prostaglandin-inhibiting drugs on neonates, use in nursing mothers should be avoided.

Pediatric Use:

Safety and effectiveness in pediatric patients below the age of 2 years have not been established. Pediatric dosing recommendations for juvenile arthritis are based on well-controlled studies (see DOSAGE AND ADMINISTRATION). These 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 (as naproxen oral suspension, see DOSAGE AND ADMINISTRATION section),with total daily dose not exceeding 15 mg/kg/day, are well tolerated in pediatric patients over 2 years of age.

ADVERSE REACTIONS:

The following adverse reactions are divided into three parts based on frequency and whether or not the possibility exists of a causal relationship, between naproxen and these adverse events. In those reactions listed as "Probable Causal Relationship" there is at least one case for each adverse reaction where there is evidence to suggest that there is causal relationship between drug usage and the reported event.

Adverse reactions reported in controlled clinical trials in 960 patients treated for rheumatoid arthritis or osteoarthritis are listed 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.

The following adverse reactions are divided into three parts based on frequency and causal relationship.

Incidence greater than 1% (Probable Causal Relationship):

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

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

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

Special Senses: tinnitus*, hearing disturbances, visual disturbances.

Cardiovascular: edema*, dyspnea*, palpitations.

General: thirst.

*Incidence of reported reaction between 3% and 9%. Those reactions occurring in less than 3% of the patients are unmarked.

Incidence less than 1% (Probable Causal Relationship):

The following adverse reactions were reported less frequently than 1% during controlled clinical trials and through voluntary reports since marketing. Those reactions observed through voluntary reporting since marketing are italicised.

Gastrointestinal: abnormal liver function tests, colitis, gastrointestinal bleeding and/or perforation, hematemesis, jaundice, pancreatitis, melena, vomiting.

Renal: glomerular nephritis, hematuria, hyperkalemia, interstitial nephritis, nephrotic syndrome, renal disease, renal failure, renal papillary necrosis.

Hematologic: agranulocytosis, eosinophilia, granulocytopenia, leukopenia, thrombocytopenia.

Central Nervous System: depression, dream abnormalities, inability to concentrate, insomnia, malaise, myalgia, muscle weakness.

Dermatologic: alopecia, photosensitive dermatitis, urticaria, skin rashes, photosensitivity reactions resembling porphyria cutanea tarda, epidermolysis bullosa.

Special Senses: hearing impairment.

Cardiovascular: congestive heart failure.

Respiratory: eosinophilic pneumonitis.

General: anaphylactoid reactions, angioneurotic edema, menstrual disorders, pyrexia (chills and fever).

Incidence less than 1% (Causal Relationship Unknown):

These observations are being listed to serve as alerting information to the physician.

Hematologic: aplastic anemia, haemolytic anemia.

Central Nervous System: aseptic meningitis, cognitive dysfunction.

Dermatologic: epidermal necrolysis, erythema multiforme, Stevens-Johnson syndrome.

Gastrointestinal: non-peptic gastrointestinal ulceration, ulcerative stomatitis.

Cardiovascular: vasculitis.

General: hyperglycemia, hypoglycemia.

OVERDOSAGE:

Significant naproxen overdosage may be characterized by drowsiness, heartburn, indigestion, nausea or vomiting. A few patients have experienced seizures, 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.

Should a patient ingest a large number of tablets accidentally or purposefully, the stomach may be emptied and usual supportive measures employed. In animals, 0.5 g/kg of activated charcoal was effective in reducing plasma levels of naproxen. Hemodialysis does not decrease the plasma concentration of naproxen because of the high degree of its protein binding.

DOSAGE AND ADMINISTRATION:

Rheumatoid Arthritis, Osteoarthritis, and Ankylosing Spondylitis:

The recommended dose of naproxen delayed-release tablets is 375 mg or 500 mg twice daily. To maintain the integrity of the enteric coating, the naproxen delayed-release tablets should not be broken, crushed or chewed during ingestion.

During long-term administration, the dose of naproxen may be adjusted up or down depending on the clinical response of the patient. A lower daily dose may suffice for long-term administration. The morning and evening doses do not have to be equal in size and the administration of the drug more frequently than twice daily is not necessary.

In patients who tolerate lower doses well, the dose may be increased to naproxen 1500 mg per day for limited periods when a higher level of anti-inflammatory/analgesic activity is required. When such patients with naproxen 1500 mg/day, the physician should observe sufficient increased clinical benefits to offset the potential increased risk (see CLINICAL PHARMACOLOGY and INDIVIDUALIZATON OF DOSAGE).

Juvenile Arthritis:

The recommended total daily dose of naproxen is approximately 10 mg/kg given in 2 divided doses (i.e., 5 mg/kg given twice a day). Naproxen tablets are not well suited to this dosage so use of naproxen oral suspension is recommended for this indication.

HOW SUPPLIED:

Naproxen delayed-release tablets are available as follows:

375 mg tablet: White, round, unscored, imprinted with "G-NP-375" on one side, in light-resistant bottles of 100 and 1000.

100's (bottle): NDC 57315-029-01

1000's (bottle): NDC 57315-029-02

500 mg tablet: White, round, unscored, imprinted with "G-NP-500" on one side, in light-resistant bottles of 100 and 1000.

100's (bottle): NDC 57315-030-01

1000's (bottle): NDC 57315-030-02

Store at 15° to 30°C (59° to 86°F) in well-closed containers; dispense in light-resistant containers.

Manufactured by:  

ALPHAPHARM PTY. LTD.

15 Garnet Street,

Carole Park, Qld. 4300

Australia

PM No: 507/5

Rev May, 2003


Naproxen (Naproxen)
PRODUCT INFO
Product Code 57315-029 Dosage Form TABLET, DELAYED RELEASE
Route Of Administration ORAL DEA Schedule
INGREDIENTS
Name (Active Moiety) Type Strength
Naproxen (Naproxen) Active 375 MILLIGRAM  In 1 TABLET
Croscarmellose Sodium Inactive  
Magnesium Stearate Inactive  
Methacrylic Acid Copolymer Inactive  
Povidone Inactive  
Water Inactive  
Simethicone Emulsion Inactive  
Sodium Hydroxide Inactive  
Talc Inactive  
Titanium Dioxide Inactive  
IMPRINT INFORMATION
Characteristic Appearance Characteristic Appearance
Color WHITE (WHITE) Score 1
Shape ROUND (ROUND) Symbol false
Imprint Code G-NP-375 Coating true
Size 16mm
PACKAGING
# NDC Package Description Multilevel Packaging
1 57315-029-02 1000 TABLET In 1 BOTTLE None
2 57315-029-01 100 TABLET In 1 BOTTLE None

Naproxen (Naproxen)
PRODUCT INFO
Product Code 57315-030 Dosage Form TABLET, DELAYED RELEASE
Route Of Administration ORAL DEA Schedule
INGREDIENTS
Name (Active Moiety) Type Strength
Naproxen (Naproxen) Active 500 MILLIGRAM  In 1 TABLET
Croscarmellose Sodium Inactive  
Magnesium Stearate Inactive  
Methacrylic Acid Copolymer Inactive  
Povidone Inactive  
Water Inactive  
Simethicone Emulsion Inactive  
Sodium Hydroxide Inactive  
Talc Inactive  
Titanium Dioxide Inactive  
IMPRINT INFORMATION
Characteristic Appearance Characteristic Appearance
Color WHITE (WHITE) Score 1
Shape ROUND (ROUND) Symbol false
Imprint Code G-NP-500 Coating true
Size 18mm
PACKAGING
# NDC Package Description Multilevel Packaging
1 57315-030-01 100 TABLET In 1 BOTTLE None
2 57315-030-02 1000 TABLET In 1 BOTTLE None

Revised: 08/2006ALPHAPHARM PTY. LTD.