AHFS Class:

• Reversible COX-1/COX-2 Inhibitors 28:08.04.04

Generic Name(s):

• Naproxen

• Naproxen Sodium

Naproxen and naproxen sodium are prototypical anti-inflammatory agents (NSAIAs) that also exhibit analgesic and antipyretic activity.

Naproxen and naproxen sodium are used to relieve mild to moderately severe pain. Conventional (immediate-release) and delayed-release (enteric-coated) tablets and suspension formulations of naproxen or naproxen sodium are used for anti-inflammatory and analgesic effects in the symptomatic treatment of rheumatoid arthritis, osteoarthritis, polyarticular juvenile idiopathic arthritis, and ankylosing spondylitis.59,104,202,204,205,206,225,269 Conventional (immediate-release) tablets and suspension formulations of naproxen or naproxen sodium also are used for the symptomatic treatment of tendinitis, bursitis, acute gout, pain, and primary dysmenorrhea.225,269 Suspension formulations of naproxen are preferred for the management of juvenile arthritis since this formulation provides maximum dosage flexibility.225,269 Because of the delayed-release properties of enteric-coated naproxen tablets, this formulation is not recommended for the management of acute pain. Extended-release naproxen sodium tablets are used for the symptomatic treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, tendinitis, bursitis, acute gout, mild to moderately severe pain, and primary dysmenorrhea.230 (Naproxen 250 mg is approximately equivalent to naproxen sodium 275 mg.) Naproxen sodium also may be used for self-medication for anti-inflammatory and analgesic effects to provide temporary relief of minor aches and pains, including those associated with arthritis, and of dysmenorrhea and for its antipyretic effect to reduce fever.200

The potential benefits and risks of naproxen therapy as well as alternative therapies should be considered prior to initiating naproxen therapy.225 The lowest possible effective dosage and shortest duration of therapy consistent with treatment goals of the patient should be employed.225

Inflammatory Diseases

Naproxen and naproxen sodium are used for anti-inflammatory and analgesic effects in the symptomatic treatment of rheumatoid arthritis, osteoarthritis, polyarticular juvenile idiopathic arthritis, and ankylosing spondylitis.59,104,202,204,205,206,225,269 Naproxen also is used in fixed combination with esomeprazole magnesium for the symptomatic treatment of rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis in adults and for the symptomatic treatment of juvenile idiopathic arthritis in adolescents 12 years of age and older weighing 38 kg or more who are at risk of developing gastric ulcers associated with NSAIA therapy.267 For information on the combined use of naproxen and esomeprazole, see Uses: Prevention of Nonsteroidal Anti-inflammatory Agent-induced Ulcers, in Esomeprazole 56:28.36.

Rheumatoid Arthritis, Juvenile Arthritis, and Osteoarthritis

When used in the treatment of rheumatoid arthritis or juvenile idiopathic arthritis, naproxen has relieved pain and stiffness, reduced swelling, and improved mobility and grip strength. In the treatment of osteoarthritis, naproxen has relieved pain and stiffness and improved knee joint function. Naproxen appears to be only palliative in these conditions and has not been shown to permanently arrest or reverse the underlying disease process. Naproxen sodium also may be used for self-medication to provide temporary relief of minor aches and pains associated with arthritis.

Most clinical evaluations of naproxen in the management of rheumatoid arthritis or osteoarthritis have shown that the anti-inflammatory and analgesic effects of usual dosages of naproxen are greater than those of placebo and about equal to those of usual dosages of salicylates, indomethacin, fenoprofen, or ibuprofen. The results of a study in patients with osteoarthritis suggested that naproxen (500 mg twice daily) was less effective than tolmetin (800 mg twice daily) in some measures of pain relief, although improvements in functional ability did not differ. In controlled studies in patients with juvenile idiopathic arthritis, the anti-inflammatory and analgesic effects of usual dosages of naproxen were comparable to those of usual dosages of aspirin,104,202,205,225 indomethacin,225 or piroxicam.206 Patient response to oral NSAIAs is variable; patients who do not respond to or cannot tolerate one NSAIA might be successfully treated with a different agent. However, NSAIAs are generally contraindicated in patients in whom sensitivity reactions (e.g., urticaria, bronchospasm, severe rhinitis) are precipitated by aspirin or other NSAIAs. (See Contraindications under Cautions.)

In the management of rheumatoid arthritis in adults, NSAIAs may be useful for initial symptomatic treatment; however, NSAIAs do not alter the course of the disease or prevent joint destruction.212,239 Disease-modifying antirheumatic drugs (DMARDs) (e.g., abatacept, hydroxychloroquine, leflunomide, methotrexate, rituximab, sulfasalazine, tocilizumab, tofacitinib, tumor necrosis factor [TNF; TNF-α] blocking agents) have the potential to reduce or prevent joint damage, preserve joint integrity and function, and reduce total health care costs, and all patients with rheumatoid arthritis are candidates for DMARD therapy.239 DMARDs should be initiated early in the disease course and should not be delayed beyond 3 months in patients with active disease (i.e., ongoing joint pain, substantial morning stiffness, fatigue, active synovitis, persistent elevation of erythrocyte sedimentation rate [ESR] or C-reactive protein [CRP], radiographic evidence of joint damage) despite an adequate regimen of NSAIAs.239 NSAIA therapy may be continued in conjunction with DMARD therapy or, depending on patient response, may be discontinued.212,239 For further information on the treatment of rheumatoid arthritis, see Uses: Rheumatoid Arthritis in Methotrexate 10:00.

Use of naproxen or its salt with aspirin is not recommended by the manufacturers. There is inadequate proof that the combination is more efficacious than either drug alone, and the potential for adverse reactions may be increased. (See Nonsteroidal Anti-inflammatory Agents under Drug Interactions.)

Ankylosing Spondylitis

When used in patients with ankylosing spondylitis, naproxen has relieved night pain, morning stiffness, and pain at rest. In a limited number of controlled studies, the anti-inflammatory and analgesic effects of usual dosages of naproxen in the symptomatic treatment of ankylosing spondylitis were greater than those of placebo and comparable to those of usual dosages of aspirin or phenylbutazone (no longer commercially available in the US).

Other Inflammatory Conditions

Naproxen has been used effectively to relieve pain, fever, redness, swelling, and tenderness in patients with acute gouty arthritis.

When used in the treatment of acute painful shoulder, the anti-inflammatory and analgesic effects of naproxen sodium are greater than those of placebo and about equal to those of indomethacin. When used in the treatment of tendinitis and bursitis, the anti-inflammatory and analgesic effects of usual dosages of naproxen sodium are comparable to those of usual dosages of oxyphenbutazone (no longer commercially available in the US).

Pain

Naproxen and its salt are used to relieve postoperative pain (including that associated with dental surgery), postpartum pain, primary dysmenorrhea, pain following insertion of an intrauterine contraceptive device, orthopedic pain, headache (including migraine), and visceral pain associated with cancer. Naproxen sodium also may be used in adults and pediatric patients 12 years of age or older for self-medication to provide temporary relief of minor aches and pains associated with the common cold, headache, toothache, muscular aches, and backache.200

There are few published studies comparing the effectiveness of naproxen and its salt with other analgesics in the relief of nonarthritic pain. In one study, a single 275-mg oral dose of naproxen sodium was as effective as a single 650-mg oral dose of aspirin in the relief of postpartum uterine pain. In another study, when used to relieve postoperative or orthopedic pain, 550 mg of oral naproxen sodium followed by 275 mg every 6 hours was at least as effective as 650 mg of acetaminophen orally every 6 hours or 50 mg of pentazocine orally every 6 hours; in this study, the onset of action appeared to be more rapid for naproxen sodium than for acetaminophen or pentazocine. In another study of patients with postoperative pain, the analgesic effects of 550 mg of oral naproxen sodium and 60 mg of oral codeine sulfate were additive (the combination was more effective than either drug alone).

Some experts state that an NSAIA (e.g., naproxen or its salt) is a reasonable first-line therapy for mild to moderate migraine attacks or for severe attacks that have responded in the past to similar NSAIAs or non-opiate analgesics.105 When used for prophylaxis† of migraine headache, naproxen and its salt appear to have a modest effect on headache frequency, intensity, and/or duration.106 For further information on management and classification of migraine headache and on efficacy of concomitant naproxen sodium and sumatriptan therapy, see Uses: Vascular Headaches, in Sumatriptan 28:32.28.

Dysmenorrhea

When used to relieve dysmenorrhea, including that which develops after insertion of an intrauterine contraceptive device, an oral dosage of 500 mg of naproxen or 550 mg of naproxen sodium followed by 250 mg of naproxen or 275 mg of naproxen sodium every 6 hours, respectively, has been reported to be more effective than placebo or aspirin (650 mg 4 times daily). In a placebo-controlled study of women with primary menorrhagia† or menorrhagia associated with intrauterine contraceptive devices†, administration of naproxen (750 mg daily for the first 2 days of menstrual bleeding followed by 500 mg daily thereafter for up to 7 days) resulted in a reduction of blood loss. In one controlled study in patients with postpartum pain, a single oral dose of 550 mg of naproxen sodium appeared to provide greater pain relief after 4 and 5 hours than 500 mg of naproxen; however, there was no difference in onset of analgesia. Naproxen sodium also may be used for self-medication to provide temporary relief of manifestations of dysmenorrhea (e.g., menstrual cramps).

Fever

Naproxen sodium is used in adults and pediatric patients 12 years of age and older for self-medication as an antipyretic.200 One study indicates that a single oral dose of naproxen (2.5 or 7.5 mg/kg) was at least as effective as a single oral dose of aspirin (15 mg/kg) in the reduction of fever in children. The results of one study suggested that the combination of naproxen sodium and ampicillin was more effective than ampicillin alone in alleviating fever, dyspnea, and coughing associated with acute respiratory infections in children.

Other Uses

Naproxen has been used in the symptomatic management of osteitis deformans† (Paget's disease of bone) and Bartter's syndrome†.

Results from a large, prospective, population-based cohort study in geriatric individuals indicate a lower prevalence of Alzheimer's disease† among patients who received an NSAIA for 2 years or longer.241,242 Similar findings have been reported from some other, but not all, observational studies.241,242,243,244,245,246

Administration

The potential benefits and risks of naproxen therapy as well as alternative therapies should be considered prior to initiating naproxen therapy.225

Naproxen and naproxen sodium are administered orally. Enteric-coated tablets of naproxen should not be broken, crushed, or chewed, so that the delayed-release properties of this formulation are maintained. Adverse GI effects may be minimized by administering the drugs with meals or milk. When used for self-medication , the manufacturer recommends that each dose of naproxen sodium be taken with a full glass of water.200 Tablets containing naproxen sodium in fixed combination with sumatriptan succinate may be administered without regard to meals; the tablets should not be split, crushed, or chewed.268 Naproxen oral suspension should be shaken gently prior to use; to ensure accurate measurement of the dose, a calibrated measuring device should always be used to administer the oral suspension.269 Tablets containing delayed-release naproxen in fixed combination with immediate-release esomeprazole magnesium should be swallowed whole with liquid and administered at least 30 minutes before meals; the tablets should not be split, chewed, crushed, or dissolved.267

Because of the delayed-release properties of enteric-coated formulations, enteric-coated preparations of naproxen are not recommended for the management of acute pain. Also, the manufacturer states that because naproxen sodium is absorbed more rapidly than naproxen, the sodium salt conventional tablet formulation is recommended for the management of acute painful conditions when prompt onset of pain relief is desired.

Dosage

The lowest possible effective dosage and shortest duration of therapy consistent with treatment goals of the patient should be employed.225 Dosage of naproxen must be carefully adjusted according to individual requirements and response, using the lowest possible effective dosage.225

Lower dosages of the drug should be considered in patients with renal or hepatic impairment or in geriatric patients.230 Use of naproxen or naproxen sodium in patients with moderate to severe renal impairment (creatinine clearance less than 30 mL/minute) is not recommended.225 Caution is advised when high dosages are required in patients with hepatic impairment.225 The commercially available preparation containing naproxen in fixed combination with esomeprazole magnesium is not recommended for patients with severe hepatic impairment because the appropriate esomeprazole dosage is not available as a fixed-ratio preparation for twice-daily dosing.267 In addition, the commercially available preparation containing naproxen sodium in fixed combination with sumatriptan succinate should not be used in patients with hepatic impairment since sumatriptan dosage cannot be appropriately adjusted.268

Patients receiving naproxen for self-medication should be advised to use the lowest effective dosage and not to exceed the recommended dosage or duration of therapy.200 (See Precautions for Self-medication under Cautions.)

Each 220, 275, 412.5, 550, or 825 mg of naproxen sodium is approximately equivalent to 200, 250, 375, 500, or 750 mg of naproxen, respectively.

Different dose strengths and formulations are not necessarily bioequivalent, and this should be considered when changing from one strength to another or from one formulation to another.225

Inflammatory Diseases

Rheumatoid Arthritis, Osteoarthritis, and Ankylosing Spondylitis

For the symptomatic treatment of osteoarthritis, rheumatoid arthritis, or ankylosing spondylitis, but excluding acute gouty arthritis), the usual adult dosage of naproxen is 250-500 mg (275-550 mg of naproxen sodium) twice daily in the morning and evening. Alternatively, 250 mg of naproxen (275 mg of naproxen sodium) may be given in the morning, and 500 mg (550 mg of the sodium salt) may be given in the evening. It is not necessary to administer either drug more often than twice daily, and morning and evening doses do not have to be equal in size.

The usual adult dosage of extended-release naproxen tablets is 750 mg or 1 g (825 mg or 1.1 g of naproxen sodium) administered once daily.230 Patients receiving other naproxen dosage forms twice daily may be switched to the extended-release naproxen sodium tablets by replacing their total daily dosage with an equal dosage of the extended-release formulation and then administered once daily.230

Subsequent dosage of naproxen or naproxen sodium should be adjusted according to the patient's response and tolerance. In patients who tolerate lower dosages well, the dosage of naproxen may be increased to 1.5 g (1.65 g of naproxen sodium) daily for limited periods of time (up to 6 months) when a greater level of anti-inflammatory and/or analgesic activity is necessary; when a dosage of 1.5 g (1.65 g of the sodium salt) daily is administered, an adequate increase in clinical benefit should be evident to justify potential increased risks associated with this dosage. Symptomatic improvement usually begins within 1 week after beginning therapy; however, 2 weeks of treatment may be required to achieve a therapeutic benefit.230

When naproxen is used in fixed combination with esomeprazole magnesium for the symptomatic relief of rheumatoid arthritis, osteoarthritis, or ankylosing spondylitis, the recommended adult dosage of naproxen is 375 or 500 mg twice daily.267

For self-medication to provide temporary relief of pain associated with arthritis, the recommended adult dosage is 200 mg of naproxen (220 mg of naproxen sodium) every 8-12 hours; therapy may be initiated with a naproxen dosage of 400 mg (440 mg of the sodium salt) within the first hour and 200 mg (220 mg of the sodium salt) 12 hours later.200 Dosage for self-medication should not exceed 400 mg of naproxen (440 mg of naproxen sodium) in any 8- or 12-hour period and 600 mg of naproxen (660 mg of the sodium salt) in any 24-hour period unless otherwise directed by a clinician.200 Such self-medication should not exceed 10 days unless otherwise directed.200

Juvenile Arthritis

For the symptomatic treatment of juvenile idiopathic arthritis, the recommended dosage of naproxen is approximately 10 mg/kg daily given in 2 divided doses.104,204,205,225,269 Because naproxen and naproxen sodium tablets are not well suited for providing the calculated pediatric dosage of the drug, naproxen oral suspension preferably should be used in this age group.208,225,269 Naproxen tablets should not be used in children weighing less than 50 kg.225,271 (See Pediatric Precautions under Cautions.)

When naproxen is used in fixed combination with esomeprazole magnesium for the symptomatic relief of juvenile idiopathic arthritis in adolescents 12 years of age and older weighing 50 kg or more, the recommended dosage of naproxen is 375 or 500 mg twice daily; in those weighing 38 to less than 50 kg, the recommended dosage of naproxen is 375 mg twice daily.267

Other Inflammatory Conditions

For the symptomatic treatment of acute gouty arthritis, the usual adult dosage of naproxen is 750 mg (825 mg of naproxen sodium) initially followed by 250 mg (275 mg of naproxen sodium) every 8 hours; therapy is continued until the attack subsides. Alternatively, in the management of acute gout, an initial dosage of 1-1.5 g of naproxen (using extended-release naproxen sodium tablets) may be used (as a single dose) on the first day, followed by 1 g given once daily until the attack subsides.230 The manufacturer states that delayed-release (enteric-coated) naproxen tablets are not recommended for treatment of acute gout because of the delayed absorption of the drug from this preparation.225 Relief of pain and tenderness and decreases in heat and swelling have been reported to occur within 24-48 hours.

For the relief of tendinitis or bursitis, the usual initial adult dose of naproxen is 500 mg (550 mg of naproxen sodium), followed by 500 mg (550 mg of the sodium salt) every 12 hours or 250 mg (275 mg of the sodium salt) every 6-8 hours as necessary.225 Total initial daily dose should not exceed 1.25 g of naproxen (1.375 g of naproxen sodium).225 Alternatively, the usual adult oral dosage of naproxen from extended-release tablets is 1 g (1.1 g of naproxen sodium) administered once daily.230 If adequate response does not occur, dosage of the extended-release tablets may be increased to 1.5 g of naproxen daily; however, such dosages should be used for a limited period only.230 Thereafter, the total daily dose should not exceed 1 g of naproxen (1.1 g of naproxen sodium).225,230

Pain and Dysmenorrhea

For relief of mild to moderate pain or dysmenorrhea, the usual initial adult dose of naproxen is 500 mg (550 mg of naproxen sodium), followed by 500 mg (550 mg of the sodium salt) every 12 hours or 250 mg (275 mg of the sodium salt) every 6-8 hours as necessary. Total initial daily dose should not exceed 1.25 g of naproxen (1.375 g of naproxen sodium). Alternatively, the usual adult oral dosage of naproxen from extended-release tablets is 1 g (1.1 g of naproxen sodium) administered once daily.230 If adequate response does not occur, dosage of the extended-release tablets may be increased to 1.5 g of naproxen daily; however, such dosages should be used for a limited period only.230 Thereafter, the total daily dose should not exceed 1 g of naproxen (1.1 g of naproxen sodium).

Alternatively, for self-medication of these conditions in adults and adolescents 12 years of age and older, a naproxen dosage of 200 mg (220 mg of naproxen sodium) every 8-12 hours can be used.200 Some patients may experience greater relief if therapy is initiated with a dose of 400 mg (440 mg of the sodium salt) within the first hour and then 200 mg (220 mg of the sodium salt) 12 hours later.200 Regardless of the regimen employed, dosage for self-medication should not exceed 400 mg of naproxen (440 mg of naproxen sodium) in any 8- or 12-hour period and 600 mg of naproxen (660 mg of the sodium salt) in any 24-hour period unless otherwise directed by a clinician.200 Self-medication of pain should not exceed 10 days unless otherwise directed.

When naproxen sodium is used in fixed combination with sumatriptan succinate for the acute management of migraine attacks in adults, the recommended dosage of naproxen sodium is 500 mg (given in fixed combination with sumatriptan 85 mg) as a single dose.268 Efficacy of more than 1 dose has not been established.268 If a second dose is administered, an interval of at least 2 hours should elapse between the first and second doses.268 No more than 2 doses (total sumatriptan dosage of 170 mg) should be administered in any 24-hour period.268 The safety of treating an average of more than 5 headaches per 30-day period has not been established.268

Fever

For self-medication of fever in adults and adolescents 12 years of age and older, the usual dosage recommended for self-medication of pain can be used.200 (See Pain and Dysmenorrhea under Dosage and Administration.) Antipyretic therapy with naproxen sodium should not exceed 3 days for self-medication unless otherwise directed by a clinician.

Cardiovascular Effects

Peripheral edema has occurred in patients receiving naproxen; congestive heart failure, palpitations, vasculitis, tachycardia, and dyspnea have occurred less frequently. Increases in blood pressure have been reported in patients receiving naproxen.218

Nonsteroidal anti-inflammatory agents (NSAIAs), including selective cyclooxygenase-2 (COX-2) inhibitors and prototypical NSAIAs, increase the risk of serious adverse cardiovascular thrombotic events, including myocardial infarction and stroke (which can be fatal), in patients with or without cardiovascular disease or risk factors for cardiovascular disease.225,500,502 Use of NSAIAs also is associated with an increased risk of heart failure.225,500

The association between cardiovascular complications and use of NSAIAs is an area of ongoing concern and study.253,264,500 Findings of an FDA review of published observational studies of NSAIAs, a meta-analysis of published and unpublished data from randomized controlled trials of these drugs, and other published information500,501,502 indicate that NSAIAs may increase the risk of serious adverse cardiovascular thrombotic events by 10-50% or more, depending on the drugs and dosages studied.500 Available data suggest that the increase in risk may occur early (within the first weeks) following initiation of therapy and may increase with higher dosages and longer durations of use.225,500,502,505,506 Although the relative increase in cardiovascular risk appears to be similar in patients with or without known underlying cardiovascular disease or risk factors for cardiovascular disease, the absolute incidence of serious NSAIA-associated cardiovascular thrombotic events is higher in those with cardiovascular disease or risk factors for cardiovascular disease because of their elevated baseline risk.225,500,502,506

Results from observational studies utilizing Danish national registry data indicated that patients receiving NSAIAs following a myocardial infarction were at increased risk of reinfarction, cardiovascular-related death, and all-cause mortality beginning in the first week of treatment.225,505 Patients who received NSAIAs following myocardial infarction had a higher 1-year mortality rate compared with those who did not receive NSAIAs (20 versus 12 deaths per 100 person-years).225,500,511 Although the absolute mortality rate declined somewhat after the first year following the myocardial infarction, the increased relative risk of death in patients who received NSAIAs persisted over at least the next 4 years of follow-up.225,511

In 2 large controlled clinical trials of a selective COX-2 inhibitor for the management of pain in the first 10-14 days following coronary artery bypass graft (CABG) surgery, the incidence of myocardial infarction and stroke was increased.225 Therefore, NSAIAs are contraindicated in the setting of CABG surgery.225

Findings from some systematic reviews of controlled observational studies and meta-analyses of data from randomized studies of NSAIAs suggest that naproxen may be associated with a lower risk of cardiovascular thrombotic events compared with other NSAIAs.258,259,260,264,500,501,502,503,506 However, limitations of these observational studies and the indirect comparisons used to assess cardiovascular risk of the prototypical NSAIAs (e.g., variability in patients' risk factors, comorbid conditions, concomitant drug therapy, drug interactions, dosage, and duration of therapy) affect the validity of the comparisons; in addition, these studies were not designed to demonstrate superior safety of one NSAIA compared with another.500 Therefore, FDA states that definitive conclusions regarding relative risks of NSAIAs are not possible at this time.500 (See Cautions: Cardiovascular Effects, in Celecoxib 28:08.04.08.)

Data from observational studies also indicate that use of NSAIAs in patients with heart failure is associated with increased morbidity and mortality.225,500,504,507 Results from a retrospective study utilizing Danish national registry data indicated that use of selective COX-2 inhibitors or prototypical NSAIAs in patients with chronic heart failure was associated with a dose-dependent increase in the risk of death and an increased risk of hospitalization for myocardial infarction or heart failure.225,500,504 In addition, findings from a meta-analysis of published and unpublished data from randomized controlled trials of NSAIAs indicated that use of selective COX-2 inhibitors or prototypical NSAIAs was associated with an approximate twofold increase in the risk of hospitalization for heart failure.225,500,501 Fluid retention and edema also have been observed in some patients receiving NSAIAs.225

There is no consistent evidence that use of low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs.225,502

GI Effects

Adverse reactions to naproxen mainly involve the GI tract. Constipation, heartburn, abdominal pain, and nausea occur in about 3-9% of patients receiving the drug. Less frequently, dyspepsia, diarrhea, stomatitis, vomiting, anorexia, colitis, peptic ulcer, GI bleeding/perforation, hematemesis, and flatulence occur. In patients with rheumatoid arthritis, adverse GI effects appear to be more frequent and more severe at a naproxen dosage of 1.5 g (1.65 g of naproxen sodium) daily than at 750 mg (825 mg of naproxen sodium) daily. The frequency of adverse GI effects in children appears to be similar to that in adults. Adverse GI effects may be minimized by administering naproxen with meals or milk.

Naproxen may reactivate latent peptic ulcer and may cause peptic ulcers in patients with no previous history of ulcers. Hemorrhage and perforation of ulcers may occur, occasionally causing fatalities. Hematemesis, GI bleeding without obvious ulcer formation, and melena also have occurred. Prodromal symptoms do not always precede GI bleeding. Ulcerative stomatitis, esophagitis, and nonpeptic GI ulceration have been reported during postmarketing experience.225 Although a causal relationship has not been directly determined, one case-control analysis suggests that NSAIAs may contribute to the formation of esophageal stricture in patients with gastroesophageal reflux.

Clinical studies of conventional versus delayed-release (enteric-coated) naproxen tablets demonstrated similar prevalence of minor GI complaints; however, individual patients may prefer one formulation over the other. In a dosage of 500 mg daily, naproxen has been reported to produce fewer adverse GI effects than 3.6-4.8 g of aspirin daily. In one study, a single dose of 550 mg of naproxen sodium produced fewer adverse GI effects than a single dose of 650 mg of aspirin. It is not known whether naproxen causes less peptic ulceration than does aspirin. In one study, the amount of GI bleeding as determined by fecal blood loss and gastroscopic evaluation in healthy adults was reported to be less with 1 g of naproxen or 1.1 g of naproxen sodium daily than with 3.25 g of aspirin daily. In another study in patients with rheumatoid arthritis, fecal blood loss following 750 mg of naproxen daily was less than that following 3.6 g of aspirin daily and no different than that during the control period. The frequency of adverse GI effects in patients receiving 500 mg of naproxen or 550 mg of naproxen sodium daily is reportedly similar to that in patients receiving 1.2 g of ibuprofen daily and less than that in patients receiving 100 mg of indomethacin daily or 2.4 g of fenoprofen daily.

Serious, sometimes fatal, adverse GI effects (e.g., bleeding, ulceration, or perforation of the esophagus, stomach, or small or large intestine) can occur at any time in patients receiving NSAIA therapy, and such effects may not be preceded by warning signs or symptoms.209,210,214,225 Only 1 in 5 patients who develop a serious upper GI adverse event while receiving an NSAIA is symptomatic.225 Therefore, clinicians should remain alert to the possible development of serious GI effects (e.g., bleeding, ulceration) in any patient receiving NSAIA therapy, and such patients should be followed chronically for the development of manifestations of such effects and advised of the importance of this follow-up.209,210,225 Patients receiving concomitant low-dose aspirin therapy for cardiovascular prophylaxis should be monitored even more closely for evidence of GI bleeding.225 In addition, patients should be advised about the signs and symptoms of serious NSAIA-induced GI toxicity and what action to take if they occur.209,210 If signs and symptoms of a serious GI event develop, additional evaluation and treatment should be initiated promptly; the NSAIA should be discontinued until appropriate diagnostic studies have ruled out a serious GI event.225

Results of studies to date are inconclusive concerning the relative risk of various prototypical NSAIAs in causing serious GI effects.209,210 In patients receiving NSAIAs and observed in clinical studies of several months' to 2 years' duration, upper GI ulcers, gross bleeding, or perforation appeared to occur in approximately 1% of patients treated for 3-6 months and in about 2-4% of those treated for 1 year.209,210,225 Longer duration of therapy with an NSAIA increases the likelihood of a serious GI event.225 However, short-term therapy is not without risk.225 High dosages of any NSAIA probably are associated with increased risk of such effects, although controlled studies documenting this probable association are lacking for most NSAIAs.209,210 Therefore, whenever use of relatively high dosages (within the recommended dosage range) is considered, sufficient benefit to offset the potential increased risk of GI toxicity should be anticipated.209,210

Studies have shown that patients with a history of peptic ulcer disease and/or GI bleeding who are receiving NSAIAs have a greater than tenfold increased risk of developing GI bleeding than patients without these risk factors.208,225,238 In addition to a history of ulcer disease, pharmacoepidemiologic studies have identified several comorbid conditions and concomitant therapies that may increase the risk for GI bleeding, including concomitant use of oral corticosteroids, anticoagulants, aspirin, or selective serotonin-reuptake inhibitors (SSRIs); longer duration of NSAIA therapy; smoking; alcohol use; older a and poor general health status.208,225,238 Risk of GI bleeding also is increased in patients with advanced liver disease and/or coagulopathy.225 Patients with rheumatoid arthritis are more likely to experience serious GI complications from NSAIA therapy than are patients with osteoarthritis.208,238,239 In addition, geriatric or debilitated patients appear to tolerate GI ulceration and bleeding less well than other individuals, and most spontaneous reports of fatal GI effects have been in such patients.225

For patients at high risk for complications from NSAIA-induced GI ulceration (e.g., bleeding, perforation), concomitant use of misoprostol can be considered for preventive therapy212,238,239,240 (See Misoprostol 56:28.28.) Alternatively, some clinicians suggest that a proton-pump inhibitor (e.g., esomeprazole, omeprazole) may be used concomitantly to decrease the incidence of serious GI toxicity associated with NSAIA therapy.212,238,239 (See Esomeprazole 56:28.36.) In one study, therapy with high dosages of famotidine (40 mg twice daily) was more effective than placebo in preventing peptic ulcers in NSAIA-treated patients; however, the effect of the drug was modest.238 In addition, efficacy of usual dosages of H₂-receptor antagonists for the prevention of NSAIA-induced gastric and duodenal ulcers has not been established.238 Therefore, most clinicians do not recommend use of H₂-receptor antagonists for the prevention of NSAIA-associated ulcers.238,239 Another approach in high-risk patients who would benefit from NSAIA therapy is use of an NSAIA that is a selective inhibitor of COX-2 (e.g., celecoxib), since these agents are associated with a lower incidence of serious GI bleeding than are prototypical NSAIAs.239 However, while celecoxib (200 mg twice daily) was comparably effective to diclofenac sodium (75 mg twice daily) plus omeprazole (20 mg daily) in preventing recurrent ulcer bleeding (recurrent ulcer bleeding probabilities of 4.9 versus 6.4%, respectively, during the 6-month study) in H. pylori -negative arthritis (principally osteoarthritis) patients with a recent history of ulcer bleeding, the protective efficacy was unexpectedly low for both regimens and it appeared that neither could completely protect patients at high risk.248,249 Additional study is necessary to elucidate optimal therapy for preventing GI complications associated with NSAIA therapy in high-risk patients.248,249

Nervous System Effects

Adverse nervous system effects of naproxen include headache, drowsiness, and dizziness, which occur in about 3-9% of patients. Vertigo, lightheadedness, inability to concentrate, mental depression, nervousness, irritability, fatigue, malaise, insomnia, sleep disorders, dream abnormalities, and aseptic meningitis may also occur. Although a causal relationship to naproxen has not been definitely established, reversible peripheral neuropathy,207 cognitive dysfunction,225 and seizures225 have occurred rarely in patients receiving the drug. The frequency of adverse nervous system effects in children appears to be similar to that in adults.

Otic and Ocular Effects

Patients receiving naproxen have experienced tinnitus and, less frequently, other hearing or visual disturbances (e.g., hearing impairment). Corneal opacity, papillitis, papilledema, and retrobulbar optic neuritis have been reported during postmarketing experience.225

Hematologic Effects

Adverse hematologic effects of naproxen include thrombocytopenia, leukopenia, granulocytopenia, and eosinophilia. Although a causal relationship to naproxen has not been established, agranulocytosis, aplastic anemia, and hemolytic anemia have occurred in patients receiving the drug. Naproxen can inhibit platelet aggregation and may prolong bleeding time. The frequency of prolonged bleeding time may be greater in children than in adults. Anemia has occurred in patients receiving NSAIAs and may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis.225

Renal and Electrolyte Effects

Renal disease, glomerulonephritis, interstitial nephritis, nephrotic syndrome, renal failure, renal papillary necrosis, dysuria, and hyperkalemia have been reported in patients receiving naproxen. Some cases of hyperkalemia in patients receiving NSAIAs have involved individuals without renal impairment; in individuals with normal renal function, hyperkalemia has been attributed to a hyporenin-hypoaldosterone state.225 Abnormal laboratory findings include hematuria and asymptomatic increases in BUN and serum creatinine. In one patient who developed increased serum creatinine concentration and decreased creatinine clearance during naproxen therapy, these measurements returned to pretreatment values following discontinuance of the drug and remained within normal limits after sulindac therapy was started. Chronic high doses of naproxen have caused nephritis and cortical and papillary necrosis in animals.

Hepatic Effects

Severe, sometimes fatal, hepatic reactions including fulminant hepatitis, liver necrosis, and hepatic failure have been reported rarely in patients receiving NSAIAs.225 Jaundice (including cholestatic jaundice which cleared promptly when naproxen was discontinued) and fatal hepatitis have been reported rarely in patients receiving naproxen. Abnormal liver function test results, including mild and generally transient increases in serum alkaline phosphatase, have occurred in some patients.

Borderline (less than 3 times the upper limit of normal) elevations of serum ALT or AST concentration may occur in up to 15% of patients treated with NSAIAs, including naproxen; meaningful (3 or more times the upper limit of normal) elevations of serum ALT or AST concentration have occurred in less than 1% of patients receiving NSAIAs in clinical studies. Naproxen should be discontinued immediately if signs or symptoms consistent with liver disease develop or if systemic manifestations (e.g., eosinophilia, rash) occur, and clinical evaluation of the patient should be performed.225 (See Hepatic Precautions under Cautions.)

Dermatologic and Sensitivity Reactions

Pruritus, skin eruptions or rashes, and ecchymoses occur frequently during naproxen administration. Sweating, photosensitive dermatitis, photosensitivity reactions resembling porphyria cutanea tarda and epidermolysis bullosa, and purpura have also occurred occasionally. The frequency of rash may be greater in children than in adults. Toxic epidermal necrolysis, erythema multiforme, Stevens-Johnson syndrome, urticaria, alopecia,225 erythema nodosum,225 fixed drug eruption,225 lichen planus,225 and pustular reaction225 have been reported during postmarketing experience. Anaphylactic reactions have been reported in patients with or without known hypersensitivity to the drug, as well as in patients with aspirin-sensitivity asthma.225

Other Adverse Effects

Thirst, myalgia, muscle weakness and cramps, pyrexia, sore throat, eosinophilic pneumonitis225 or colitis,213 anaphylactoid reactions,225 pancreatitis,225 and menstrual disturbances also have been reported during naproxen therapy. Hypoglycemia, hyperglycemia, angioedema, systemic lupus erythematosus,225 vasculitis,225 asthma,225 pulmonary edema,225 and female infertility225 have been reported during postmarketing experience. In a patient receiving naproxen in combination with aspirin, infective symptoms associated with an empyema appeared to be suppressed.

Precautions and Contraindications

With the exception of precautions related to the sodium content of naproxen sodium, the cautions associated with naproxen sodium use are the same as those for naproxen use. Each 220-, 275-, 412.5, 550-, or 825-mg naproxen sodium tablet contains about 0.87, 1, 1.5, 2, or 3 mEq of sodium, respectively, and each mL of the commercially available naproxen suspension contains about 0.3 mEq of sodium; this should be considered in patients whose sodium intake must be restricted. Multiple naproxen-containing preparations (e.g., naproxen conventional and delayed-release [enteric-coated] tablets, naproxen suspension, naproxen sodium conventional and extended-release tablets) should not be used concomitantly, as all of these products circulate in the plasma as naproxen anion and may result in naproxen toxicity.

When naproxen or naproxen sodium is used in fixed combination with other drugs (e.g., esomeprazole magnesium, sumatriptan succinate), the usual cautions, precautions, and contraindications associated with the concomitant agent must be considered in addition to those associated with naproxen.267,268

Patients should be advised that naproxen, like other NSAIAs, is not free of potential adverse effects, including some that can cause discomfort, and that more serious effects (e.g., myocardial infarction, stroke, GI bleeding), which may require hospitalization and may even be fatal, can occur.209,210,225,500

Patients should be advised to read the medication guide for NSAIAs that is provided to the patient each time the drug is dispensed.225

Cardiovascular Precautions

NSAIAs increase the risk of serious adverse cardiovascular thrombotic events.225,258,259,260,264,500,502 (See Cardiovascular Effects under Cautions.) To minimize the potential risk of adverse cardiovascular events, the lowest effective dosage and shortest possible duration of therapy should be employed.225,500 Some clinicians suggest that it may be prudent to avoid use of NSAIAs whenever possible in patients with cardiovascular disease.505,511,512,516 Patients receiving NSAIAs (including those without previous symptoms of cardiovascular disease) should be monitored for the possible development of cardiovascular events throughout therapy.225,500 Patients should be informed about the signs and symptoms of serious cardiovascular toxicity (chest pain, dyspnea, weakness, slurring of speech) and instructed to seek immediate medical attention if such toxicity occurs.225,500 Naproxen should be avoided in patients with recent myocardial infarction unless the benefits of therapy are expected to outweigh the risk of recurrent cardiovascular thrombotic events; if naproxen is used in such patients, the patient should be monitored for cardiac ischemia.225

There is no consistent evidence that concomitant use of low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs.225,502 Concomitant use of aspirin and an NSAIA increases the risk for serious GI events.225 (See Nonsteroidal Anti-inflammatory Agents under Drug Interactions.)

Use of NSAIAs can result in the onset of hypertension or worsening of preexisting hypertension; either of these occurrences may contribute to the increased incidence of cardiovascular events.225 Patients receiving NSAIAs may have an impaired response to diuretics (i.e., thiazide or loop diuretics), angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, or β-adrenergic blocking agents.225 Blood pressure should be monitored closely during initiation of NSAIA therapy and throughout therapy.225

Because NSAIAs increase morbidity and mortality in patients with heart failure, the manufacturer states that naproxen should be avoided in patients with severe heart failure unless the benefits of therapy are expected to outweigh the risk of worsening heart failure; if naproxen is used in such patients, the patient should be monitored for worsening heart failure.225 Some experts state that use of NSAIAs should be avoided whenever possible in patients with reduced left ventricular ejection fraction and current or prior symptoms of heart failure.507 Patients receiving NSAIAs should be advised to inform their clinician if they experience symptoms of heart failure, including dyspnea, unexplained weight gain, and edema.225 Use of NSAIAs may diminish the cardiovascular effects of certain drugs used to treat heart failure and edema (e.g., diuretics, ACE inhibitors, angiotensin II receptor antagonists).225 (See Antihypertensive Agents and also Diuretics under Drug Interactions.)

GI Precautions

The risk of potentially serious adverse GI effects should be considered in patients receiving naproxen, particularly in patients receiving chronic therapy with the drug.209,210 Since peptic ulceration and/or GI bleeding have been reported in patients receiving the drug, patients should be advised to promptly report signs or symptoms of GI ulceration or bleeding to their clinician.225

To minimize the potential risk of adverse GI effects, the lowest effective dosage and shortest possible duration of therapy should be employed, and use of more than one NSAIA at a time should be avoided.225 (See Nonsteroidal Anti-inflammatory Agents under Drug Interactions.) In addition, use of NSAIAs should be avoided in patients at higher risk (see GI Effects under Cautions) unless benefits of therapy are expected to outweigh the increased risk of bleeding; for patients who are at high risk, as well as for those with active GI bleeding, alternative therapy other than an NSAIA should be considered.225

Hepatic Precautions

Elevations in serum ALT may be the most sensitive indicator of NSAIA-induced liver dysfunction. Patients who experience signs and/or symptoms suggestive of liver dysfunction or an abnormal liver function test result while receiving naproxen should be evaluated for evidence of the development of a severe hepatic reaction. Severe reactions, including jaundice and/or fatal hepatitis, have occurred during therapy with naproxen. Although such reactions are rare, naproxen should be discontinued immediately if clinical signs and symptoms consistent with liver disease develop or if systemic manifestations (e.g., eosinophilia, rash) occur. Patients receiving naproxen should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, anorexia, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, flu-like syndrome) and advised to discontinue naproxen therapy and seek immediate medical care if they experience such symptoms.225

Lower dosages of naproxen should be considered in patients with hepatic impairment. Naproxen has not been evaluated in patients with hepatic impairment, and the manufacturer states that caution is advised when large dosages of the drug are required in patients with hepatic impairment; dosage adjustment may be necessary.225 Although total plasma concentrations of naproxen are decreased in patients with chronic alcoholic liver disease, concentrations of the unbound drug are increased.225

Renal Precautions

Because renal prostaglandins may have a supportive role in maintaining renal perfusion in patients with prerenal conditions, administration of an NSAIA to such patients may cause a dose-dependent reduction in prostaglandin formation and thereby precipitate overt renal decompensation. Patients at greatest risk of this reaction include those with impaired renal function, heart failure, or hepatic dysfunction; those with extracellular fluid depletion (e.g., patients receiving diuretics); those taking an ACE inhibitor or angiotensin II receptor antagonist concomitantly; and geriatric patients.225 Patients should be advised to consult their clinician promptly if unexplained weight gain or edema occurs.225 Fluid depletion should be corrected prior to initiation of naproxen therapy, and renal function should be monitored during naproxen therapy in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia.225 Recovery of renal function to pretreatment levels usually occurs following discontinuance of NSAIA therapy. Some clinicians recommend that renal function be monitored periodically in patients receiving long-term NSAIA therapy.

The renal effects of naproxen may hasten the progression of renal dysfunction in patients with preexisting renal disease.225 Patients with preexisting renal disease should be monitored for worsening renal function.225

Lower dosages of naproxen should be considered in patients with renal impairment. Naproxen has not been evaluated in patients with renal impairment; however, naproxen and its metabolites and conjugates are excreted mainly by the kidneys, and the potential exists for naproxen metabolites to accumulate in patients with renal impairment.225 Elimination of naproxen is decreased in patients with severe renal impairment.225

The manufacturers state that use of naproxen in patients with advanced renal disease should be avoided unless the benefits of therapy are expected to outweigh the risk of worsening renal function; use of the drug in those with moderate to severe renal impairment is not recommended.225 If naproxen is used in patients with advanced renal disease, close monitoring of renal function is recommended.225

Precautions Related to Dermatologic or Hypersensitivity Reactions

Anaphylactic reactions have been reported in patients receiving naproxen.225 Patients receiving naproxen should be informed of the signs and symptoms of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat) and advised to seek immediate medical attention if an anaphylactic reaction develops.225

Serious skin reactions (e.g., exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis) can occur in patients receiving NSAIAs.225 These serious skin reactions may occur without warning; patients should be advised to consult their clinician if skin rash and blisters, fever, or other signs of hypersensitivity reaction (e.g., pruritus) occur.225 NSAIAs should be discontinued at the first appearance of rash or any other sign of hypersensitivity.225

Multi-organ hypersensitivity (also known as drug reaction with eosinophilia and systemic symptoms [DRESS]), a potentially fatal or life-threatening syndrome, has been reported in patients receiving NSAIAs.225 The clinical presentation is variable, but typically includes eosinophilia, fever, rash, lymphadenopathy, and/or facial swelling, possibly associated with other organ system involvement such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis.225 Symptoms may resemble those of an acute viral infection.225 Early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present in the absence of rash.225 If such signs or symptoms develop, naproxen should be discontinued and the patient evaluated immediately.225

Hematologic Precautions

NSAIAs, including naproxen, may increase the risk of bleeding.225 Patients with certain coexisting conditions such as coagulation disorders and those receiving concomitant therapy with anticoagulants, antiplatelet agents, or serotonin-reuptake inhibitors may be at increased risk and should be monitored for signs of bleeding.225 (See Drug Interactions.)

Since naproxen can inhibit platelet aggregation, patients who may be adversely affected by a prolongation of bleeding time should be carefully observed during naproxen therapy.

If signs and/or symptoms of anemia occur during therapy with naproxen, hemoglobin concentration and hematocrit should be determined.225 In addition, hemoglobin concentration should be determined periodically during long-term naproxen therapy in individuals with an initial hemoglobin concentration of 10 g/dL or less.225

Precautions for Self-medication

Patients receiving naproxen for self-medication should be advised to use the lowest effective dosage and not to exceed the recommended dosage or duration of therapy.200 Unless otherwise directed by a clinician, patients receiving naproxen for self-medication should be advised to discontinue the drug and consult a clinician if pain persists for more than 10 days or fever persists for longer than 3 days.200 Patients should not use naproxen for self-medication immediately before or after cardiac surgery or if they have experienced an allergic reaction to any analgesic or antipyretic.200

Patients receiving naproxen for self-medication should be advised to consult a clinician before initiating naproxen if they have experienced adverse effects associated with any analgesic or antipyretic; if they have a GI disorder, coagulation disorder, hypertension, cardiac disease, asthma, hepatic cirrhosis, or renal disease; if they have had a stroke; if they have a history of bleeding events or GI disorders (e.g., heartburn, peptic ulcer); if they are receiving therapy with a diuretic, an anticoagulant, a corticosteroid, or any other NSAIA-containing preparation; if they consume 3 or more alcohol-containing drinks per day; or if they are 60 years of age or older.200 Patients receiving the drug for self-medication should consult a clinician or pharmacist before initiating naproxen if they are under a clinician's care for any continuing serious medical condition; are taking aspirin for reduction of cardiovascular risk, or are receiving any other drugs on a regular basis.200

Patients should be advised to stop taking naproxen for self-medication and consult their clinician if symptoms of GI bleeding (e.g., faintness, vomiting blood, bloody or black stools, persistent stomach pain) develop; if cardiac symptoms or symptoms of stroke (e.g., chest pain, difficulty breathing, weakness in one part or side of the body, slurred speech, leg swelling) occur; if they have difficulty swallowing or feel like a “pill is stuck in their throat”; if any new symptoms occur during self-medication with the drug; or if redness or swelling is present in the painful area.200 Patients should be advised that the risk of GI bleeding is increased if they are 60 years of age or older, have a GI disorder (e.g., history of GI bleeding or peptic ulceration), are receiving an anticoagulant or corticosteroid, are receiving another NSAIA (including aspirin) concomitantly, generally consume 3 or more alcohol-containing drinks per day, or exceed the recommended dosage or duration of naproxen therapy.200 In addition, patients should be advised that NSAIAs (except aspirin) increase the risk of myocardial infarction, heart failure, and stroke and that the risk is increased if they exceed the recommended dosage or duration of naproxen therapy.200,500 Patients receiving low-dose aspirin should be advised that naproxen can interfere with the antiplatelet effect of aspirin.200

Other Precautions

Patients receiving long-term NSAIA therapy should have a complete blood cell count and chemistry profile performed periodically.225

Naproxen can interfere with the antiplatelet effect of low-dose aspirin.261,262,263,500 Patients receiving low-dose aspirin for its cardioprotective effects should be informed of this potential interaction.500 (See Nonsteroidal Anti-inflammatory Agents under Drug Interactions.)

Because NSAIAs have caused adverse ocular effects, patients who experience visual disturbances or changes during naproxen therapy should have an ophthalmologic examination.225

The possibility that the antipyretic and anti-inflammatory effects of NSAIAs may mask the usual signs and symptoms of infection or other diseases should be considered.

Contraindications

Naproxen is contraindicated in patients with known hypersensitivity (e.g., anaphylaxis, serious dermatologic reactions) to the drug or any ingredient in the formulation.225 In addition, NSAIAs, including naproxen, generally are contraindicated in patients in whom asthma, urticaria, or other sensitivity reactions are precipitated by aspirin or other NSAIAs, since there is potential for cross-sensitivity between NSAIAs and aspirin, and severe, rarely fatal, anaphylactic reactions to NSAIAs have been reported in these patients.225 Although NSAIAs generally are contraindicated in these patients, the drugs have occasionally been used in NSAIA-sensitive patients who have undergone desensitization. Because patients with asthma may have aspirin-sensitivity asthma, patients with asthma but without known aspirin sensitivity who are receiving naproxen should be monitored for changes in manifestations of asthma.225 In patients with asthma, aspirin sensitivity is manifested principally as bronchospasm and usually is associated with nasal polyps; the association of aspirin sensitivity, asthma, and nasal polyps is known as the aspirin triad.225 Patients who are considering use of naproxen for self-medication should be advised that naproxen is contraindicated in patients who have experienced asthma, urticaria, or other sensitivity reaction to other analgesics or antipyretics.200 For a further discussion of cross-sensitivity of NSAIAs, see Cautions: Sensitivity Reactions, in the Salicylates General Statement 28:08.04.24.

NSAIAs are contraindicated in the setting of CABG surgery.225

Pediatric Precautions

Safety and efficacy of naproxen in children younger than 2 years of age have not been established.225 Pediatric dosage recommendations for juvenile idiopathic arthritis are based on well-controlled studies.225 There are no adequate efficacy or dose-response data for other pediatric conditions, but clinical experience in juvenile idiopathic arthritis and other use experience indicate that single doses of 2.5-5 mg/kg with a total daily dose not exceeding 15 mg/kg are safe in children older than 2 years of age.225 Naproxen sodium should not be used for self-medication in children younger than 12 years of age unless otherwise directed by a clinician.

Safety and efficacy of extended-release naproxen sodium tablets in children have not been established.230

Overdosage and toxicity (including death) have been reported in children younger than 2 years of age receiving nonprescription (over-the-counter, OTC) preparations containing antihistamines, cough suppressants, expectorants, and nasal decongestants alone or in combination for relief of symptoms of upper respiratory tract infection.265,266 Such preparations also may contain analgesics and antipyretics (e.g., naproxen).265 There is limited evidence of efficacy for these preparations in this age group, and appropriate dosages (i.e., approved by FDA) have not been established.265 Therefore, FDA stated that nonprescription cough and cold preparations should not be used in children younger than 2 years of a the agency continues to assess safety and efficacy of these preparations in older children. Meanwhile, because children 2-3 years of age also are at increased risk of overdosage and toxicity, some manufacturers of oral nonprescription cough and cold preparations recently have agreed to voluntarily revise the product labeling to state that such preparations should not be used in children younger than 4 years of age. FDA recommends that parents and caregivers adhere to the dosage instructions and warnings on the product labeling that accompanies the preparation if administering to children and consult with their clinician about any concerns. Clinicians should ask caregivers about use of nonprescription cough and cold preparations to avoid overdosage. For additional information on precautions associated with the use of cough and cold preparations in pediatric patients, see Cautions: Pediatric Precautions in Pseudoephedrine 12:12.12.

Geriatric Precautions

Geriatric patients are at increased risk for NSAIA-associated serious adverse cardiovascular, GI, and renal effects.225 Geriatric individuals appear to tolerate GI ulceration and bleeding less well than other individuals, and many of the spontaneous reports of fatal adverse GI effects in patients receiving NSAIAs involve geriatric individuals.225 If the anticipated benefits of naproxen therapy outweigh the potential risks, naproxen should be initiated at the lower end of the dosing range and patients should be monitored for adverse effects.225

Lower dosages of naproxen should be considered in geriatric patients. Although the total plasma concentrations of naproxen in geriatric patients are similar to those attained in younger adults, the unbound plasma fraction of the drug is increased in geriatric patients when compared with that in younger adults.225,230 The clinical relevance of this finding is unclear, although the increase in unbound naproxen concentrations could be associated with an increase in the frequency of adverse events at any given dosage in some geriatric patients.225 Naproxen should be used with caution in geriatric patients requiring high dosages; some adjustment of dosage may be needed.225

In 2 double-blind clinical trials evaluating hepatic and renal tolerability of naproxen (375 or 750 mg twice daily for up to 6 months), 17% of patients were 65 years of age and older, while less than 2% were 75 years of age and older.225 Although transient abnormalities in hepatic and renal function test results were observed in some patients, no age-related differences in the frequency of such abnormalities were observed.225

Naproxen and its metabolites are eliminated substantially by the kidneys, and individuals with renal impairment may be at increased risk of toxic reactions to the drug.225,230 Because geriatric patients frequently have decreased renal function, particular attention should be paid to naproxen dosage, and it may be useful to monitor renal function in these patients.225,230

Carcinogenicity

A 2-year study in rats was performed to evaluate the carcinogenic potential of naproxen at 8, 16, or 24 mg/kg daily (50, 100, or 150 mg/m², respectively); the maximum dose used was 0.28 times the human systemic exposure at the recommended dose. There was no evidence of carcinogenicity.

Pregnancy, Fertility, and Lactation

Pregnancy

Use of NSAIAs during pregnancy at about 30 weeks of gestation or later can cause premature closure of the fetal ductus arteriosus, and use at about 20 weeks of gestation or later has been associated with fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment.225,1200 Because of these risks, use of NSAIAs should be avoided in pregnant women at about 30 weeks of gestation or later; if NSAIA therapy is necessary between about 20 and 30 weeks of gestation, the lowest effective dosage and shortest possible duration of treatment should be used.225,1200 Monitoring of amniotic fluid volume via ultrasound examination should be considered if the duration of NSAIA treatment exceeds 48 hours; if oligohydramnios occurs, the drug should be discontinued and follow-up instituted according to clinical practice.225,1200 Pregnant women should be advised to avoid use of NSAIAs beginning at 20 weeks' gestation unless otherwise advised by a clinician; they should be informed that NSAIAs should be avoided beginning at 30 weeks' gestation because of the risk of premature closure of the fetal ductus arteriosus and that monitoring for oligohydramnios may be necessary if NSAIA therapy is required for longer than 48 hours' duration between about 20 and 30 weeks of gestation.225,1200

Known effects of NSAIAs on the human fetus during the third trimester of pregnancy include prenatal constriction of the ductus arteriosus, tricuspid incompetence, and pulmonary hypertension; nonclosure of the ductus arteriosus during the postnatal period (which may be resistant to medical management); and myocardial degenerative changes, platelet dysfunction with resultant bleeding, intracranial bleeding, renal dysfunction or renal failure, renal injury or dysgenesis potentially resulting in prolonged or permanent renal failure, oligohydramnios, GI bleeding or perforation, and increased risk of necrotizing enterocolitis.1202

Fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment has been observed, on average, following days to weeks of maternal NSAIA use, although oligohydramnios has been observed infrequently as early as 48 hours after initiation of NSAIA therapy.225,1200 Oligohydramnios is often, but not always, reversible (generally within 3-6 days) following discontinuance of NSAIA therapy.225,1200 Complications of prolonged oligohydramnios may include limb contracture and delayed lung maturation.225,1200 A limited number of case reports have described maternal NSAIA use and neonatal renal dysfunction, in some cases irreversible, without oligohydramnios.225,1200 Some cases of neonatal renal dysfunction have required treatment with invasive procedures such as exchange transfusion or dialysis.225,1200 Deaths associated with neonatal renal failure have been reported.1200 Methodologic limitations of these postmarketing studies and case reports include lack of a control group; limited information regarding dosage, duration, and timing of drug exposure; and concomitant use of other drugs.225 These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAIA use.225 Available data on neonatal outcomes generally involved preterm infants, and the extent to which certain reported risks can be generalized to full-term infants is uncertain.225

Animal data indicate that prostaglandins have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization.225 In animal studies, inhibitors of prostaglandin synthesis, such as naproxen, were associated with increased pre- and post-implantation losses.225 Prostaglandins also have an important role in fetal kidney development.225 In animal studies, inhibitors of prostaglandin synthesis impaired kidney development at clinically relevant doses.225

Reproduction studies of naproxen in rats at 20 mg/kg daily (125 mg/m², 0.23 times the human systemic exposure), rabbits at 20 mg/kg daily (220 mg/m², 0.27 times the human systemic exposure), and mice at 170 mg/kg daily (510 mg/m², 0.28 times the human systemic exposure) have not revealed evidence of harm to the fetus. Severe hypoxemia due to persistent pulmonary hypertension has occurred in infants whose mothers received naproxen to delay parturition. Neonatal death also has been reported when the drug was used to prevent preterm labor; autopsy of a neonate showed brain hemorrhage, multiple gastric ulcers, extensive GI bleeding, and an adverse cardiovascular effect known to be associated with use of NSAIAs.219 In addition, severe hyponatremia, water retention, cerebral irritation, and paralytic ileus was reported in a neonate whose mother ingested 5 g of naproxen 8 hours before delivery; it has been suggested that naproxen adversely affected renal function.219 Renal dysfunction and abnormal prostaglandin E concentrations in premature infants also have been reported.

Effects of naproxen during labor or delivery have not been studied.225 In animal studies, NSAIAs, including naproxen, inhibited prostaglandin synthesis, delayed parturition, and increased the incidence of stillbirth.225

Fertility

Use of NSAIAs may delay or prevent ovarian follicular rupture, which has been associated with reversible infertility in some women.225 Reversible delays in ovulation have been observed in limited studies in women receiving NSAIAs, and animal studies indicate that inhibitors of prostaglandin synthesis can disrupt prostaglandin-mediated follicular rupture required for ovulation.225 Therefore, withdrawal of NSAIAs should be considered in women who are experiencing difficulty conceiving or are undergoing evaluation of infertility.225

Reproduction studies of naproxen in rats at 20 mg/kg daily (125 mg/m², 0.23 times the human systemic exposure), rabbits at 20 mg/kg daily (220 mg/m², 0.27 times the human systemic exposure), and mice at 170 mg/kg daily (510 mg/m², 0.28 times the human systemic exposure) have not revealed evidence of impaired fertility. Information on the effects of naproxen on fertility in humans is lacking. At least one human case was reported in which ejaculatory dysfunction occurred during naproxen therapy and was reversed upon discontinuing the drug; a definite causal relationship was not established.

Lactation

Naproxen is distributed into milk at concentrations of approximately 1% of peak plasma concentrations of the drug.225

The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for naproxen and any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.225

Protein-bound Drugs

Because naproxen is highly protein bound, it theoretically could be displaced from binding sites by, or it could displace from binding sites, other protein-bound drugs such as oral anticoagulants, hydantoins, other nonsteroidal anti-inflammatory agents (NSAIAs; including aspirin), sulfonamides, and sulfonylureas.225 Patients receiving naproxen with any of these drugs should be observed for adverse effects, and dosage should be adjusted as needed.

Drugs Affecting Gastric pH

Concomitant administration of naproxen and aluminum hydroxide or magnesium oxide antacids may result in delayed absorption of naproxen.225 However, when delayed-release (enteric-coated) naproxen tablets were administered with antacid (buffering capacity of 54 mEq), peak plasma concentrations of naproxen were unchanged; the mean time to peak concentration was reduced, but not to a substantial extent (from 5.6 hours under fasted conditions to 5 hours with antacid).225 The manufacturers state that concomitant administration of naproxen and antacids is not recommended.225,230

In a controlled study in healthy adults, concomitant oral administration of naproxen and cimetidine did not appear to alter the pharmacokinetics of either drug and did not affect the inhibition of gastric acid output by cimetidine.

Anticoagulants and Thrombolytic Agents

The effects of warfarin and NSAIAs on GI bleeding are synergistic.225 Concomitant use of naproxen and warfarin is associated with a higher risk of GI bleeding compared with use of either agent alone.225

Administration of naproxen with warfarin results in a slight increase in free warfarin in serum, but does not affect the hypoprothrombinemic effect of warfarin. Naproxen should be used with caution in patients receiving any anticoagulant or thrombolytic agent (e.g., streptokinase), and patients should be carefully monitored for signs of bleeding.

Antidiabetic Agents

Results of a study in patients with diabetes mellitus showed no interference by naproxen on the effect of tolbutamide on plasma glucose concentrations.

Antihypertensive Agents

Concomitant use of NSAIAs with angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, or β-adrenergic blocking agents may reduce the blood pressure response to the antihypertensive agent.225 Therefore, blood pressure should be monitored to ensure that target blood pressure is achieved.225

Concomitant use of naproxen with ACE inhibitors or angiotensin II receptor antagonists in geriatric patients or patients with volume depletion or renal impairment may result in reversible deterioration of renal function, including possible acute renal failure; such patients should be monitored for signs of worsening renal function.225 Patients receiving concomitant therapy with naproxen and ACE inhibitors or angiotensin II receptor antagonists should be adequately hydrated, and renal function should be assessed when concomitant therapy is initiated and periodically thereafter.225

Cholestyramine

Concomitant administration of naproxen and cholestyramine may result in delayed absorption of naproxen.225 Concomitant administration of naproxen and cholestyramine is not recommended.225,230

Cyclosporine

Concomitant use of naproxen and cyclosporine may increase the nephrotoxic effects of cyclosporine.225 Patients should be monitored for signs of worsening renal function.225

Digoxin

Concomitant use of naproxen and digoxin has been reported to result in increased serum concentrations and prolonged half-life of digoxin.225 Serum digoxin concentrations should be monitored.225

Diuretics

NSAIAs can reduce the natriuretic effects of furosemide or thiazide diuretics, and concomitant use of diuretics and NSAIAs may increase the risk of NSAIA-associated nephrotoxicity in dehydrated patients.225 The reduction in natriuretic effect may be related to inhibition of renal prostaglandin synthesis.225 Patients receiving concomitant NSAIA and diuretic therapy should be monitored for worsening renal function and for adequacy of diuretic and antihypertensive effects.225

Lithium

Naproxen may increase serum lithium concentrations and reduce renal lithium clearance.221,222,223,224 Concomitant use of NSAIAs and lithium has increased trough lithium concentrations by 15% and decreased renal lithium clearance by approximately 20%.225 If naproxen and lithium are administered concurrently, the patient should be observed closely for signs of lithium toxicity, and serum lithium concentrations should be monitored carefully during the initial stages of combined therapy or subsequent dosage adjustment.221,222,223,224 In addition, appropriate adjustment of lithium dosage may be required when therapy with naproxen is discontinued.221

Methotrexate

Concomitant use of NSAIAs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction).225 Severe, sometimes fatal, toxicity has occurred following administration of an NSAIA concomitantly with methotrexate (principally high-dose therapy) in patients with various malignant neoplasms or rheumatoid arthritis. The toxicity was associated with elevated and prolonged blood concentrations of methotrexate. The exact mechanism of the interaction remains to be established, but it has been suggested that NSAIAs may inhibit renal elimination of methotrexate, possibly by decreasing renal perfusion via inhibition of renal prostaglandin synthesis or by competing for renal elimination. Patients receiving concomitant naproxen and methotrexate therapy should be monitored for methotrexate toxicity.225 (See Drug Interactions: Nonsteroidal Anti-inflammatory Agents, in Methotrexate 10:00.)

Nonsteroidal Anti-inflammatory Agents

In controlled clinical trials, concomitant use of NSAIAs and analgesic dosages of aspirin did not produce any greater therapeutic effect than use of NSAIAs alone.225 However, concomitant use of aspirin and an NSAIA increases the risk for bleeding and serious GI events.225 Because of the potential for increased adverse effects, concomitant use of naproxen with other NSAIAs or with analgesic dosages of aspirin generally is not recommended.225

Administration of aspirin with NSAIAs may decrease protein binding of the NSAIA, but clearance of the free (unbound) NSAIA does not appear to be altered.225 The clinical importance of this pharmacokinetic interaction has not been established.225

Some NSAIAs (e.g., ibuprofen, naproxen) can interfere with the antiplatelet effect of low-dose aspirin.500 Ibuprofen can interfere with the antiplatelet effect of low-dose aspirin (81 mg daily; immediate-release preparation) when the drugs are administered concomitantly.261,262 The interaction can be minimized by appropriate timing of ibuprofen administration relative to that of immediate-release, low-dose aspirin.261,262 (See Drug Interactions: Nonsteroidal Anti-inflammatory Agents, in Ibuprofen 28:08.04.92.) In one study, concomitant administration of naproxen (500 mg) and low-dose aspirin (100 mg) also interfered with the antiplatelet effect of aspirin.261,263 In another study, interference by naproxen sodium (220 mg once or twice daily) with the antiplatelet effect of low-dose, immediate-release aspirin was observed to be most marked during the washout period following discontinuance of naproxen.225 A similar interaction might be expected with higher (i.e., prescription-strength) dosages of naproxen and enteric-coated, low-dose aspirin, although the timing of peak interference may occur later because of the longer washout period.225 The observed interaction was greater when naproxen was administered 30 minutes prior to administration of immediate-release, low-dose aspirin and minimal when immediate-release, low-dose aspirin was administered 30 minutes prior to naproxen administration.225 Because there may be an increased risk of cardiovascular events following discontinuance of naproxen, use of an NSAIA that does not interfere with the antiplatelet effect of aspirin or use of an analgesic other than an NSAIA, when appropriate, should be considered for intermittent analgesic therapy in patients receiving low-dose aspirin.225

Naproxen is not a substitute for low-dose aspirin therapy for prophylaxis of cardiovascular events, and patients receiving antiplatelet agents such as aspirin concomitantly with NSAIAs should be monitored closely for bleeding.225 There is no consistent evidence that use of low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs.225,502

Pemetrexed

Concomitant use of naproxen and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal toxicity, and GI toxicity.225 Administration of NSAIAs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided beginning 2 days before and continuing through 2 days after pemetrexed administration.225 In the absence of data regarding potential interactions between pemetrexed and NSAIAs with longer half-lives (e.g., meloxicam, nabumetone), administration of NSAIAs with longer half-lives should be interrupted beginning at least 5 days before and continuing through 2 days after pemetrexed administration.225 Patients with renal impairment with a creatinine clearance of 45-79 mL/minute should be monitored for myelosuppression, renal toxicity, and GI toxicity if they receive concomitant naproxen and pemetrexed therapy.225

Probenecid

Administration of probenecid with naproxen substantially increases the plasma half-life of naproxen and plasma naproxen concentrations. In one study, the plasma half-life of naproxen increased to an average of 37 hours and plasma naproxen concentrations increased by an average of 50% when the drugs were administered concomitantly. It was suggested that probenecid interfered with the plasma clearance of naproxen by inhibiting the formation of glucuronide conjugates of naproxen, as well as inhibiting its renal clearance. Patients receiving concomitant therapy with probenecid and naproxen should be monitored, and dosage should be adjusted as needed.225

Serotonin-reuptake Inhibitors

Serotonin release by platelets plays an important role in hemostasis.225 Results of case-control and epidemiologic cohort studies indicate that concomitant use of NSAIAs and drugs that interfere with serotonin reuptake may potentiate the risk of bleeding beyond that associated with an NSAIA alone.225 Patients receiving concomitant therapy with naproxen and selective serotonin-reuptake inhibitors (SSRIs) or selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs) should be monitored for signs of bleeding.225

Sucralfate

Concomitant administration of naproxen and sucralfate may result in delayed absorption of naproxen.225 Concomitant administration of sucralfate with naproxen is not recommended.225,230

Other Drugs

Naproxen should be used cautiously, if at all, with other drugs that might potentiate the adverse GI effects.

Laboratory Test Interferences

Naproxen or its metabolites may cause falsely elevated urinary 17-ketogenic steroid concentrations by interfering with the m -dinitrobenzene reagent used in the test. Although 17-hydroxycorticosteroid measurements (Porter-Silber method) are not significantly altered, withdrawal of naproxen for 72 hours before testing has been recommended.

Naproxen may also interfere with some urinary assays of 5-hydroxyindoleacetic acid (5-HIAA).

Acute Toxicity

Limited information is available on the acute toxicity of naproxen or naproxen sodium.

Pathogenesis

The acute dose of naproxen or naproxen sodium associated with life-threatening toxicity in humans is not known.219 The oral LD₅₀ of naproxen is 4110, 1234, more than 1000, and 543 mg/kg in hamsters, mice, dogs, and rats, respectively.

Manifestations

The most frequent manifestations following acute nonsteroidal anti-inflammatory agent (NSAIA) overdosage include lethargy, drowsiness, nausea, vomiting, and epigastric pain.225 GI bleeding has occurred, and hypertension, acute renal failure, respiratory depression, and coma have occurred rarely.225 A few patients have experienced seizures, but a causal relationship to the drug is unclear.225 Because naproxen sodium may be absorbed rapidly, high and early blood concentrations of the drug should be anticipated following naproxen sodium overdosage.225

There have been several cases of naproxen overdosage in children which have resulted in acute toxicity.219 Acute renal failure and hyperkalemia were reported in a 2-year-old child with juvenile arthritis who received a naproxen sodium dosage of 20 mg/kg daily for 1 month.219 Death occurred in an 8-month-old child following administration of 110-440 mg of naproxen sodium for 5 days for fever and upper respiratory infection.219 A 2-year-old child recovered after ingesting up to 2 g of naproxen, hydrogen peroxide, and eucalyptus oil and who developed drowsiness, ataxia, and prolonged bleeding time.219 Another 2-year-old child developed dyspepsia after ingesting 625 mg of naproxen.219 In addition, seizures were reported in a 5-year-old child who ingested an unknown amount of naproxen sodium.219

Most cases of naproxen overdosage have been reported in adults.219 Adverse GI effects (e.g., heartburn, vomiting) and seizures usually occur in these patients; drowsiness and prolongation of clotting time also may occur.219 The incidence of adverse effects in adults may differ from those in children since rash and prolonged bleeding time appear to occur more frequently in children while other reactions occur more frequently in adults; the incidence of adverse GI and CNS effects are similar.219

One patient who ingested 25 g of naproxen experienced mild nausea and indigestion. Life-threatening adverse effects are uncommon; however, seizures, apnea, metabolic acidosis, and impaired renal function have been reported following overdosage of naproxen.219 One death due to CNS depression has been attributed to naproxen overdosage.

Treatment

Treatment of acute toxicity associated with naproxen overdosage is mainly supportive.225 There is no specific antidote.225 If there is evidence that the drug was ingested recently (within 4 hours) or in large amounts (e.g., 5-10 times the recommended dosage), induction of emesis, administration of activated charcoal, and/or osmotic catharsis should be considered in symptomatic patients.225 Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful in enhancing elimination of naproxen because of the high protein binding of the drug.225

Pharmacology

Naproxen has pharmacologic actions similar to those of other prototypical NSAIAs. The drug exhibits anti-inflammatory, analgesic, and antipyretic activity. The exact mechanisms have not been clearly established, but many of the actions appear to be associated principally with the inhibition of prostaglandin synthesis. Naproxen inhibits the synthesis of prostaglandins in body tissues by inhibiting cyclooxygenase; at least 2 isoenzymes, cyclooxygenase-1 (COX-1) and -2 (COX-2) (also referred to as prostaglandin G/H synthase-1 [PGHS-1] and -2 [PGHS-2], respectively), have been identified that catalyze the formation of prostaglandins in the arachidonic acid pathway. Naproxen, like other prototypical NSAIAs, inhibits both COX-1 and COX-2.231,232,233,234,235,236 Although the exact mechanisms have not been clearly established, NSAIAs appear to exert anti-inflammatory, analgesic, and antipyretic activity principally through inhibition of the COX-2 isoenzyme; COX-1 inhibition presumably is responsible for the drugs' unwanted effects on GI mucosa and platelet aggregation.231,232,233,234,235,236

Anti-inflammatory, Analgesic, and Antipyretic Effects

The anti-inflammatory, analgesic, and antipyretic effects of naproxen and other NSAIAs, including selective inhibitors of COX-2 (e.g., celecoxib, rofecoxib), appear to result from inhibition of prostaglandin synthesis. While the precise mechanism of the anti-inflammatory and analgesic effects of NSAIAs continues to be investigated, these effects appear to be mediated principally through inhibition of the COX-2 isoenzyme at sites of inflammation with subsequent reduction in the synthesis of certain prostaglandins from their arachidonic acid precursors.231,232,233,234,235,236

Naproxen stabilizes lysosomal membranes and inhibits the response of neutrophils to chemotactic stimuli. The drug does not possess glucocorticoid or adrenocorticoid-stimulating properties.

There is no evidence that long-term therapy with naproxen results in tolerance to or physical dependence on the drug. The drug probably cannot suppress the abstinence syndrome in opiate-dependent patients.

Naproxen lowers body temperature in patients with fever. Although the mechanism of the antipyretic effect of NSAIAs is not known, it has been suggested that suppression of prostaglandin synthesis in the CNS (probably in the hypothalamus) may be involved.

Genitourinary and Renal Effects

Naproxen-induced inhibition of prostaglandin synthesis may result in decreased frequency and intensity of uterine contractility. Prostaglandins E₂ and F_2α increase the amplitude and frequency of uterine contractions in pregnant women; current evidence suggests that primary dysmenorrhea is also mediated by these prostaglandins. Whether the increased production of prostaglandins associated with primary dysmenorrhea is mediated by COX-1 or COX-2 remains to be determined.237 Blood concentrations of a metabolite of prostaglandin F_2α have been found to decrease in women with dysmenorrhea who were receiving naproxen. Therapy with naproxen has been effective in relieving menstrual pain and has reduced blood loss in women with menorrhagia, probably by inhibiting the formation of these prostaglandins. Administration of naproxen during late pregnancy may prolong gestation by inhibiting uterine contractions.

Naproxen has been reported to adversely affect renal function. (See Renal and Electrolyte Effects under Cautions.) The mechanisms of adverse renal effects of naproxen have not been determined, but may involve inhibition of renal synthesis of prostaglandins.

Naproxen does not appear to have uricosuric activity.

GI Effects

Naproxen can cause gastric mucosal damage which may result in ulceration and/or bleeding. (See GI Effects under Cautions.) These gastric effects have been attributed to inhibition of the synthesis of prostaglandins produced by COX-1.231,232,233,234,235,236,238 Other factors possibly involved in NSAIA-induced gastropathy include local irritation, promotion of acid back-diffusion into gastric mucosa, uncoupling of oxidative phosphorylation, and enterohepatic recirculation of the drugs.235,238

Epidemiologic and laboratory studies suggest that NSAIAs may reduce the risk of colon cancer.235 Although the exact mechanism by which NSAIAs may inhibit colon carcinogenesis remains to be determined, it has been suggested that inhibition of prostaglandin synthesis may be involved.235

Hematologic Effects

Although naproxen can inhibit platelet aggregation and may prolong bleeding time, it does not affect prothrombin or whole blood clotting time. (See Hematologic Effects under Cautions.) In one study, the drug inhibited the second phase of platelet aggregation induced by adenosine diphosphate or epinephrine. Like aspirin and other prototypical NSAIAs, the effects of naproxen on platelets appear to be associated with the inhibition of the synthesis of prostaglandins produced by COX-1.235

Pharmacokinetics

Naproxen pharmacokinetics have not been determined in individuals with renal or hepatic impairment, nor in children younger than 5 years of age.225 Pharmacokinetics of the drug in the delayed-release (enteric-coated) formulation have not been determined in individuals younger than 18 years of age.

Absorption

Preparations of naproxen differ in their pattern of absorption, owing to the chemical form of naproxen (i.e., the base or sodium salt) and the formulation used. When administered as the acid or the sodium salt, naproxen is completely absorbed from the GI tract; the sodium salt is absorbed more rapidly than the acid. Oral bioavailability of naproxen is 95%. There appears to be no difference in bioavailability between a single 500-mg conventional tablet and two 250-mg conventional tablets of naproxen. Commercially available formulations of naproxen (i.e., conventional tablets, delayed-release tablets, oral suspension) are bioequivalent in terms of extent of absorption (i.e., area under the curve [AUC]) and peak plasma concentrations; however, the rate of absorption varies depending on the formulation used. When naproxen (either as conventional or delayed-release tablets) or naproxen sodium (either as conventional or extended-release tablets) is taken with food, the rate but not the extent of absorption of the drug is decreased. Studies to date indicate that antacids may have variable, but probably clinically insignificant, effects on absorption of naproxen (either as conventional or delayed-release tablets) or naproxen sodium.

The manufacturers state that peak plasma concentrations of the drug occur in 2-4 hours following oral administration of naproxen as conventional tablets; peak plasma concentration occurs 1-4 hours following administration of the oral suspension. In several studies, following oral administration of a single 500-mg dose of naproxen (as one 500-mg or two 250-mg conventional tablets) to fasting, healthy adults, mean peak plasma concentrations of the drug ranged from 62-96 mcg/mL and occurred at 1.5-2 hours. The manufacturers state that peak plasma concentrations of the drug occur in 1-2 hours following oral administration of naproxen sodium as conventional tablets. Following oral administration of a single 550-mg dose of naproxen sodium as a conventional tablet (equivalent to 500 mg of naproxen) to a group of fasting, healthy adults, mean peak plasma concentrations of the drug were 70 mcg/mL and occurred at about 1 hour. In children 5-16 years of age, plasma naproxen concentrations following a single 5- to 10-mg/kg dose of the suspension are similar to those attained in healthy adults following a 500-mg dose.59,203,225 Steady-state plasma concentrations of naproxen are achieved within 4-5 days.

Commercially available delayed-release (enteric-coated) tablets of naproxen (EC-Naprosyn^®) contain the drug within a copolymer coating dispersion. Dissolution of the coating is pH-dependent, with the most rapid dissolution occurring at pH above 6; no dissolution occurs below pH 4. The coating is designed to release the drug in the higher pH environment of the small intestine, avoiding dissolution in the more acidic environment of the stomach. Naproxen is well-absorbed from the enteric-coated formulation. Peak plasma concentration usually is reached about 4-6 (range: 2-12) hours following oral administration of the first dose of the enteric-coated formulation. A crossover study of oral administration of naproxen as conventional or delayed-release tablets in a dosage of 500 mg twice daily in fasted, healthy individuals demonstrated that after one week, only time to peak plasma concentration differed between the two formulations (1.9 versus 4 hours for conventional versus delayed-release tablets, respectively); there were no differences in peak plasma concentration or extent of absorption (i.e., AUC).

Commercially available tablets of naproxen and esomeprazole magnesium (Vimovo^®) contain a delayed-release (enteric-coated) naproxen core surrounded by an immediate-release layer of esomeprazole magnesium.267 The tablet is designed to release esomeprazole in the stomach prior to dissolution of naproxen in the small intestine.267 At naproxen dosages of 375 or 500 mg twice daily, the fixed-combination tablets are bioequivalent (based on AUC and peak plasma concentration) to enteric-coated preparations of naproxen.267 Peak steady-state plasma concentrations of naproxen are reached about 3 hours after administration of the fixed-combination tablet.267 Administration of the fixed-combination tablets with a high-fat meal substantially delays naproxen absorption and modestly decreases peak plasma concentrations of the drug.267

Commercially available extended-release tablets of naproxen sodium (Naprelan^®) contain an immediate-release component (about 30% of the total dose) and an extended-release component comprised of microparticles that slowly release the drug.230 The tablet matrix rapidly disintegrates in the stomach, and the microparticles are dispersed throughout the small intestine and into the proximal large intestine allowing absorption of the drug throughout the GI tract.230 Naproxen is well absorbed from naproxen sodium extended-release tablets, with a reported bioavailability of about 95%; peak steady-state plasma naproxen concentrations usually are reached in about 3-5 hours following oral administration.230 The absorption rate from extended-release naproxen sodium tablets is slower than from conventional tablets.230 Prolonged drug absorption from extended-release tablets allows for once-daily dosing with this formulation.230

Following oral administration of fixed-combination tablets containing naproxen sodium 500 mg and sumatriptan 85 mg, peak plasma naproxen concentrations are about 36% lower and the time to peak plasma naproxen concentrations is delayed by about 4 hours compared with oral administration of naproxen sodium as conventional 550-mg tablets; the extent of exposure to naproxen (i.e., AUC) is similar for the 2 formulations.268 Administration of the fixed-combination tablets with food does not substantially affect the bioavailability of naproxen.268

Plasma naproxen concentrations of 30-90 mcg/mL reportedly are required for anti-inflammatory or analgesic effect. In a group of patients with rheumatoid arthritis, the anti-inflammatory effect of naproxen was positively correlated with serum naproxen concentrations, although no such relationship was found for adverse effects. Onset of pain relief can begin within 1 hour in patients receiving naproxen (as conventional tablets) and within 30 minutes in patients receiving naproxen sodium (as conventional tablets), as evidenced by reduction in pain intensity scores, increase in pain relief scores, decrease in the number of patients requiring additional analgesic medication, and delay in time to remedication. In a comparative study in patients with postpartum uterine cramping, there was no difference between the drugs in onset of analgesia; both drugs provided pain relief within 1 hour. Peak analgesia occurs within 1 hour with naproxen sodium and within 2 hours with naproxen. The duration of action of both drugs is generally 7-12 hours. Because of the delayed absorption of enteric-coated naproxen tablets, onset of analgesia may be delayed.

Distribution

The volume of distribution of naproxen is 0.16 L/kg. In one study, the apparent volume of distribution of naproxen averaged about 8.3 L in healthy adults and about 11.9 L in patients with severe renal failure (serum creatinine 5.4-12.5 mg/dL).

After therapeutic doses, naproxen is more than 99% bound to plasma proteins. When naproxen binding sites become saturated (at twice daily doses of 500 mg or more), plasma free drug concentrations increase and may result in increased urinary clearance rates. Therefore, plasma naproxen concentrations tend to plateau when dosage exceeds 500 mg twice daily. In a study in patients with severe renal failure, binding of naproxen to serum proteins was decreased compared to healthy adults; the decreased binding may have accounted for an increase in metabolism and apparent volume of distribution of the drug observed in these patients. In patients with chronic alcoholic liver disease, total plasma concentrations of naproxen are decreased while concentrations of the unbound drug are increased.225 Total naproxen concentrations are unchanged in geriatric individuals, but concentrations of the unbound drug are increased;230 the trough concentration of unbound naproxen in geriatric individuals reportedly is 0.12-0.19% of the total naproxen concentration, compared with 0.05-0.075% in younger individuals.225

Naproxen crosses the placenta. Naproxen is also distributed into milk in concentrations of about 1% of simultaneous maternal plasma drug concentrations.

Elimination

In healthy adults, the plasma half-life of naproxen reportedly ranges from 12-17 hours.225,230 The plasma half-life and elimination of the drug appear to be similar in children and adults.59,200,202,203,208 Clearance of naproxen is 0.13 mL/minute per kg.

Naproxen is extensively metabolized in the liver by cytochrome P-450 (CYP) isoenzymes 1A2 and 2C9 to 6-desmethylnaproxen.225,230,267 Approximately 95% of the drug is excreted in urine as unchanged naproxen (less than 1%) and 6-desmethylnaproxen (less than 1%) and their glucuronide or other conjugates (66-92%). Some data suggest that renal excretion of unchanged naproxen may be negligible or absent; previously reported concentrations of unchanged drug may reflect rapid hydrolysis of conjugates during collection, storage, and handling of urine samples. The half-life of naproxen metabolites and conjugates is shorter than 12 hours.

Naproxen metabolites may accumulate in patients with renal impairment.225 Elimination of naproxen is reduced in patients with severe renal impairment.225 A small amount (less than 5%) of the drug is excreted in feces.

Chemistry and Stability

Chemistry

Naproxen, a propionic acid derivative, is a prototypical anti-inflammatory agent (NSAIA). The drug is structurally and pharmacologically related to fenoprofen and ibuprofen.

Naproxen is commercially available as the acid and as the sodium salt. Each 275 mg of naproxen sodium is approximately equivalent to 250 mg of naproxen and each 220 mg of naproxen sodium is approximately equivalent to 200 mg of naproxen. The acid occurs as a white to off-white, practically odorless, crystalline powder and is practically insoluble in water at low pH, freely soluble in water at high pH, and freely soluble in alcohol. Naproxen sodium occurs as a white to creamy white, crystalline powder and is freely soluble in water at neutral pH and sparingly soluble in alcohol. The apparent pK_a of naproxen is 4.15. Each 220-, 275-, 412.5-, 550-, or 825-mg tablet of naproxen sodium contains about 0.87, 1, 1.5, 2, or 3 mEq of sodium, respectively, and each 5 mL of the commercially available naproxen suspension contains about 1.5 mEq each of sodium and chloride.

Naproxen is commercially available as conventional tablets, delayed-release (enteric-coated) tablets, and oral suspension.225,269 Naproxen sodium is commercially available as conventional tablets, extended-release tablets, and liquid-filled capsules.200,225,230,270 Extended-release tablets of naproxen sodium (Naprelan^®) contain an immediate-release component (about 30% of the total dose) and an extended-release component comprised of microparticles that slowly release the drug.230 Fixed-combination tablets of naproxen and esomeprazole magnesium contain a delayed-release (enteric-coated) naproxen core surrounded by an immediate-release layer of esomeprazole magnesium.267

Stability

Commercially available naproxen conventional and delayed-release (enteric-coated) tablets should be stored in well-closed, light-resistant containers at 15-30°C. Extended-release naproxen sodium tablets should be stored in well-closed containers at 20-25°C but may be exposed to temperatures ranging from 15-30°C.230 Naproxen oral suspension should be stored in light-resistant containers at 20-25°C but may be exposed to temperatures ranging from 15-30°C; temperatures exceeding 40°C should be avoided.269 Naproxen sodium conventional tablets should be stored in well-closed containers at 15-30°C. Fixed-combination tablets containing delayed-release naproxen and immediate-release esomeprazole magnesium should be protected from moisture and stored in well-closed containers at 25°C but may be exposed to temperatures ranging from 15-30°C.267 Fixed-combination tablets containing naproxen sodium and sumatriptan succinate should be stored in the original container with the desiccant packet at 25°C but may be exposed to temperatures ranging from 15-30°C; the tablets should not be repackaged.268

Naproxen and naproxen sodium preparations containing the equivalent of 250 mg of naproxen or more per retail package should be stored in child-resistant containers in order to limit the potential toxicity associated with accidental ingestion in children.219

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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