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 delayed-release tablets in patients with a recent mi unless the benefits are expected to outweigh the risk of recurrent cv thrombotic events. if naproxen delayed-release 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 delayed-release 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 "flu-like" symptoms). if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue naproxen delayed-release tablets immediately, and perform a clinical evaluation of the patient. hypertension nsaids, including naproxen delayed-release tablets can lead to onset of new 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 delayed-release tablets in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. if naproxen delayed-release tablets are used in patients with severe heart failure, monitor patients for signs of worsening heart failure. renal toxicity and hyperkalemia renal toxicity 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 an nsaid 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, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ace inhibitors or arbs, and the elderly. discontinuation of nsaid therapy is usually followed by recovery to the pretreatment state no information is available from controlled clinical studies regarding the use of naproxen delayed-release tablets in patients with advanced renal disease. the renal effects of naproxen delayed-release tablets may hasten the progression of renal dysfunction in patients with preexisting renal disease. correct volume status in dehydrated or hypovolemic patients prior to initiating naproxen delayed-release tablets. monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of naproxen delayed-release tablets ( see precautions; drug interactions ). avoid the use of naproxen delayed-release tablets in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. if naproxen delayed-release tablets are used in patients with advanced renal disease, monitor patients for signs of worsening renal function. hyperkalemia increases in serum potassium concentration, including hyperkalemia, have been reported with use of nsaids, even in some patients without renal impairment. in patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state. anaphylactic reactions naproxen has been associated with anaphylactic reactions in patients with and without known hypersensitivity to naproxen and in patients with aspirin-sensitive asthma ( see contraindications , warnings; exacerbation of asthma related to aspirin sensitivity ) . exacerbation of asthma related to aspirin sensitivity a subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other nsaids. because cross-reactivity between aspirin and other nsaids has been reported in such aspirin-sensitive patients, naproxen delayed-release tablets are contraindicated in patients with this form of aspirin sensitivity ( see contraindications ) . when naproxen delayed-release tablets are used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. serious skin reactions nsaids, including naproxen, can cause serious skin adverse reactions such as exfoliative dermatitis, stevens-johnson syndrome (sjs), and toxic epidermal necrolysis (ten), which can be fatal. these serious events may occur without warning. inform patients about the signs and symptoms of serious skin reactions and to discontinue the use of naproxen delayed-release tablets at the first appearance of skin rash or any other sign of hypersensitivity. naproxen delayed-release tablets are contraindicated in patients with previous serious skin reactions to nsaids (see contraindications ). premature closure of fetal ductus arteriosus naproxen may cause premature closure of the fetal ductus arteriosus. avoid use of nsaids, including naproxen delayed-release tablets, in pregnant women starting at 30 weeks of gestation (third trimester) (see precautions; pregnancy ). hematologic toxicity anemia has occurred in nsaid-treated patients. this may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. if a patient treated with naproxen delayed-release tablets has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. nsaids, including naproxen delayed-release tablets, may increase the risk of bleeding events. co-morbid conditions such as coagulation disorders, or concomitant use of warfarin and other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (ssris) and serotonin norepinephrine reuptake inhibitors (snris) may increase this risk. monitor these patients for signs of bleeding ( see precautions; drug interactions ).

blets dissolves in the small intestine rather than in the stomach, the absorption of the drug is delayed compared to the 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 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 dosage and administration

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. three 6-week, double-blind, multicenter studies with naproxen delayed-release tablets (375 mg or 500 mg twice a day, n=385) and naproxen immediate-release tablets (375 mg or 500 mg twice a day, 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. 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.