sk for an adverse cv event in nsaid-treated patients, use the lowest effective dose for the shortest duration possible. physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous cv symptoms. patients should be informed about the symptoms of serious cv events and the steps to take if they occur. there is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious cv thrombotic events associated with nsaid use. the concurrent use of aspirin and an nsaid, such as naproxen, increases the risk of serious gastrointestinal (gi) events (see warnings; gastrointestinal bleeding, ulceration, and perforation) . status post coronary artery bypass graft (cabg) surgery two large, controlled, clinical trials of a cox-2 selective nsaid for the treatment of pain in the first 10 to 14 days following cabg surgery found an increased incidence of myocardial infarction and stroke. nsaids are contraindicated in the setting of cabg (see contraindications ). post-mi patients observational studies conducted in the danish national registry have demonstrated that patients treated with nsaids in the post-mi period were at increased risk of reinfarction, cv-related death, and all-cause mortality beginning in the first week of treatment. in this same cohort, the incidence of death in the first year post-mi was 20 per 100 person years in nsaid-treated patients compared to 12 per 100 person years in non-nsaid exposed patients. although the absolute rate of death declined somewhat after the first year post-mi, the increased relative risk of death in nsaid users persisted over at least the next four years of follow-up. avoid the use of naproxen tablets in patients with a recent mi unless the benefits are expected to outweigh the risk of recurrent cv thrombotic events. if naproxen tablets are used in patients with a recent mi, monitor patients for signs of cardiac ischemia. gastrointestinal bleeding, ulceration, and perforation nsaids, including naproxen cause serious gastrointestinal (gi) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, 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 gi adverse event on nsaid therapy, is symptomatic. upper gi ulcers, gross bleeding, or perforation caused by nsaids occured in approximately 1% of patients treated for 3 to 6 months, and in about 2% to 4% of patients treated for one year. however, even short-term nsaid therapy is not without risk. risk factors for gi bleeding, ulceration, and perforation patients with a prior history of peptic ulcer disease and/or gi bleeding who used nsaids had a greater than 10-fold increased risk for developing a gi bleed compared to patients without these risk factors. other factors that increase the risk of gi bleeding in patients treated with nsaids include longer duration of nsaid therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (ssris); smoking; use of alcohol; older age; and poor general health status. most postmarketing reports of fatal gi events occurred in elderly or debilitated patients. additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for gi bleeding. strategies to minimize the gi risks in nsaid-treated patients: use the lowest effective dosage for the shortest possible duration. avoid administration of more than one nsaid at a time. avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. for such patients, as well as those with active gi bleeding, consider alternate therapies other than nsaids. remain alert for signs and symptoms of gi ulceration and bleeding during nsaid therapy. if a serious gi adverse event is suspected, promptly initiate evaluation and treatment, and discontinue naproxen tablets until a serious gi adverse event is ruled out. in the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of gi bleeding ( see precautions ; drug interactions ). hepatotoxicity elevations of alt or ast (three or more times the upper limit of normal [uln]) have been reported in approximately 1% of patients in clinical trials. in addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis and hepatic failure have been reported. elevations of alt or ast (less than three times uln) may occur in up to 15% of patients taking nsaids including naproxen. inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flulike" symptoms). if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue naproxen tablets immediately, and perform a clinical evaluation of the patient. hypertension nsaids, including naproxen tablets, can lead to new onset of hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of cv events. patients taking angiotensin converting enzyme (ace) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking nsaids (see precautions ; drug interactions) . monitor blood pressure (bp) during the initiation of nsaid treatment and throughout the course of therapy. heart failure and edema the coxib and traditional nsaid trialists’ collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalization for heart failure in cox-2 selective-treated patients and nonselective nsaid-treated patients compared to placebo-treated patients. in a danish national registry study of patients with heart failure, nsaid use increased the risk of mi, hospitalization for heart failure, and death. additionally, fluid retention and edema have been observed in some patients treated with nsaids. use of naproxen may blunt the cv effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ace inhibitors, or angiotensin receptor blockers [arbs]) ( see precautions ; drug interactions) . avoid the use of naproxen tablets in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. if naproxen tablets are used in patients with severe heart failure, monitor patients for signs of worsening heart failure.

ng. consider emesis and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. for additional information about overdosage treatment contact a poison control center (1-800-222-1222). dosage and administration carefully consider the potential benefits and risks of naproxen tablets 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; gastrointestinal bleeding, ulceration, and perforation ). after observing the response to initial therapy with naproxen tablets, the dose and frequency should be adjusted to suit an individual patient’s needs. different dose strengths and formulations (i.e., tablets, suspension) of the drug are not necessarily bioequivalent. this difference should be taken into consideration when changing formulation. although naproxen tablets, naproxen suspension, naproxen delayed-released tablets, and naproxen sodium tablets all circulate in the plasma as naproxen, they have pharmacokinetic differences that may affect onset of action. onset of pain relief can begin within 1 hour in patients taking naproxen. 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; hepatotoxicity , and renal toxicity and hyperkalemia , and precautions ; geriatric use ). geriatric patients 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. patients with moderate to severe renal impairment naproxen-containing products are not recommended for use in patients with moderate to severe and severe renal impairment (creatinine clearance <30 ml/min) (see warnings: renal effects ). rheumatoid arthritis, osteoarthritis and ankylosing spondylitis naproxen tablets 250 mg or 375 mg or 500 mg twice daily twice daily 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. 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/day for limited periods of up to 6 months when a higher level of anti-inflammatory/analgesic activity is required. when treating such patients with naproxen 1500 mg/day, the physician should observe sufficient increased clinical benefits 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 naproxen tablets may not allow for the flexible dose titration needed in pediatric patients with juvenile arthritis. a liquid formulation may be more appropriate. in pediatric patients, doses of 5 mg/kg/day produced plasma levels of naproxen similar to those seen in adults taking 500 mg of naproxen (see clinical pharmacology ). the recommended total daily dose of naproxen is approximately 10 mg/kg given in 2 divided doses. one-half of the 250 mg tablet will be needed for dosing lower-weight children. dosing with naproxen tablets is not appropriate for children weighing less than 25 kilograms. management of pain, primary dysmenorrhea, and acute tendonitis and bursitis because the sodium salt of naproxen is more rapidly absorbed, naproxen sodium is recommended for the management of acute painful conditions when prompt onset of pain relief is desired. naproxen may also be used. the recommended starting dose of naproxen is 500 mg, followed by 500 mg every 12 hours or 250 mg every 6 to 8 hours as required. the initial total daily dose should not exceed 1250 mg of naproxen. thereafter, the total daily dose should not exceed 1000 mg of naproxen. acute gout the recommended starting dose is 750 mg of naproxen tablets followed by 250 mg every 8 hours until the attack has subsided.

area comparison), and mice at 170 mg/kg/day (0.6 times the maximum recommended human daily dose based on body surface area comparison) with no evidence of impaired fertility or harm to the fetus due to the drug. based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. in animal studies, administration of prostaglandin synthesis inhibitors such as naproxen resulted in increased pre- and post-implantation loss. labor and delivery there are no studies on the effects of naproxen tablets during labor or delivery. in animal studies, nsaids, including naproxen, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. nursing mothers the naproxen anion has been found in the milk of lactating women at a concentration equivalent to approximately 1% of maximum naproxen concentration in plasma. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for naproxen tablets and any potential adverse effects on the breastfed infant from the naproxen tablets or from the underlying maternal condition females and males of reproductive potential based on the mechanism of action, the use of prostaglandin-mediated nsaids, including naproxen, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin- mediated follicular rupture required for ovulation. small studies in women treated with nsaids have also shown a reversible delay in ovulation consider withdrawal of nsaids, including naproxen tablets, in women who have difficulties conceiving or who are undergoing investigation of infertility. 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 ). 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 (as naproxen suspension, see dosage and administration ), with total daily dose not exceeding 15 mg/kg/day, are well tolerated in pediatric patients over 2 years of age. safety and effectiveness in pediatric patients below the age of 2 years have not been established. geriatric use elderly patients, compared to younger patients, are at greater risk for nsaid-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. if the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects (see warnings; cardiovascular thrombotic events, gastrointestinal bleeding, ulceration, and perforation, hepatotoxicity , renal toxicity and hyperkalemia, precautions; laboratory monitoring) . 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 nonsteroidal anti-inflammatory drugs. elderly or debilitated patients seem to tolerate peptic ulceration or bleeding less well when these events do occur. most spontaneous reports of fatal gi events are in the geriatric population (see warnings; gastrointestinal bleeding, ulceration, and perforation ). 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 toxicity and hyperkalemia ).

f-life of naproxen is unchanged across products ranging 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 naproxen tablets, usp after administration of naproxen tablets, peak plasma levels are attained in 2 to 4 hours. distribution 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 css 36.5, 49.2 and 56.4 mg/l with 500, 1000 and 1500 mg daily doses of naproxen, respectively). the naproxen anion has been found in the milk of lactating women at a concentration equivalent to approximately 1% of maximum naproxen concentration in plasma (see precautions: nursing mothers) . elimination metabolism naproxen is extensively metabolized in the liver to 6-0-desmethyl naproxen, and both parent and metabolites do not induce metabolizing enzymes. both naproxen and 6-0-desmethyl naproxen are further metabolized to their respective acylglucuronide conjugated metabolites. excretion 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 (<1%), 6-0-desmethyl naproxen (<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. small amounts, 3% or less of the administered dose, are excreted in the feces. in patients with renal failure metabolites may accumulate (see warnings ; renal toxicity and hyperkalemia) . 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 suspension (see dosage and administration ) 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. pharmacokinetic parameters appear to be similar following administration of naproxen tablets in pediatric patients. geriatric patients studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly, although the unbound fraction is < 1% of the total naproxen concentration. unbound trough naproxen concentrations in elderly subjects have been reported to range from 0.12% to 0.19% of total naproxen concentration, compared with 0.05% to 0.075% in younger subjects. the clinical significance of this finding is unclear, although it is possible that the increase in free naproxen concentration could be associated with an increase in the rate of adverse events per a given dosage in some elderly patients. race pharmacokinetic differences due to race have not been studied. hepatic impairment naproxen pharmacokinetics has not been determined in subjects with hepatic insufficiency. 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 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. renal impairment 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. elimination of naproxen is decreased in patients with severe renal impairment. naproxen-containing products are not recommended for use in patients with moderate to severe and severe renal impairment (creatinine clearance <30 ml/min) ( see warnings ; renal toxicity and hyperkalemia ). drug interaction studies aspirin: when nsaids were administered with aspirin, the protein binding of nsaids were reduced, although the clearance of free nsaid was not altered. the clinical significance of this interaction is not known. see table 1 for clinically significant drug interactions of nsaids with aspirin (see precautions ; drug interactions) .

standard formulations of naproxen 375 mg twice a day (750 mg a day) vs 750 mg twice a day (1500 mg/day), 9 patients in the 750 mg group terminated prematurely because of adverse events. nineteen patients in the 1500 mg group terminated prematurely because of adverse events. most of these adverse events were gastrointestinal events. 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 effects (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. in patients with acute gout, a favorable response to naproxen was shown by significant clearing of inflammatory changes (e.g., decrease in swelling, heat) within 24 to 48 hours, as well as by relief of pain and tenderness. naproxen has been studied in patients with mild to moderate pain secondary to postoperative, orthopedic, postpartum episiotomy and uterine contraction pain and dysmenorrhea. onset of pain relief can begin within 1 hour in patients taking naproxen and within 30 minutes in patients taking naproxen sodium. analgesic effect was shown by such measures as reduction of pain intensity scores, increase in pain relief scores, decrease in numbers of patients requiring additional analgesic medication, and delay in time to remedication. the analgesic effect has been found to last for up to 12 hours. 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. in 51 cr blood loss and gastroscopy studies with normal volunteers, daily administration of 1000 mg of naproxen has been demonstrated to cause statistically significantly less gastric bleeding and erosion than 3250 mg of aspirin. geriatric patients the hepatic and renal tolerability of long-term naproxen administration was studied in two double-blind clinical trials involving 586 patients. of the patients studied, 98 patients were age 65 and older and 10 of the 98 patients were age 75 and older. naproxen was administered at doses of 375 mg twice daily or 750 mg twice daily for up to 6 months. transient abnormalities of laboratory tests assessing hepatic and renal function were noted in some patients, although there were no differences noted in the occurrence of abnormal values among different age groups.

at 20° to 25°c (68° to 77°f); [see usp controlled room temperature]. dispense in tight, light-resistant containers. *all brand names mentioned are registered trademark of their respective owners and are not of exelan pharmaceuticals, inc. rev: 06/2016