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Naproxen

Class: Other Nonsteroidal Anti-inflammatory Agents
CAS Number: 22204-53-1
Brands: Aleve, Anaprox, Naprelan, Naprosyn

Medically reviewed by Drugs.com on Oct 18, 2021. Written by ASHP.

Warning

    Cardiovascular Risk
  • Increased risk of serious (sometimes fatal) cardiovascular thrombotic events (e.g., MI, stroke). Risk may occur early in treatment and may increase with duration of use. (See Cardiovascular Thrombotic Effects under Cautions.)

  • Contraindicated in the setting of CABG surgery.

    GI Risk
  • Increased risk of serious (sometimes fatal) GI events (e.g., bleeding, ulceration, perforation of the stomach or intestine). Serious GI events can occur at any time and may not be preceded by warning signs and symptoms. Geriatric individuals and patients with a history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events. (See GI Effects under Cautions.)

Introduction

Prototypical NSAIA; propionic acid derivative.

Uses for Naproxen

Consider potential benefits and risks of naproxen therapy as well as alternative therapies before initiating therapy with the drug. Use lowest effective dosage and shortest duration of therapy consistent with the patient’s treatment goals.

Inflammatory Diseases

Symptomatic treatment of osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis. May be used in fixed combination with esomeprazole in patients at risk of developing gastric ulcers associated with NSAIA therapy.

Symptomatic treatment of tendinitis, bursitis, and acute gout.

Management of juvenile idiopathic arthritis in children ≥2 years of age. May be used in fixed combination with esomeprazole in adolescents ≥12 years of age weighing ≥38 kg who are at risk of developing gastric ulcers associated with NSAIA therapy.

Pain

Relief of pain.

NSAIAs considered first-line agents for mild to moderate migraine attacks or for severe attacks that have responded in the past to NSAIAs or nonopiate analgesics.

Self-medication in adolescents ≥12 years of age and adults for the temporary relief of minor aches and pain associated with the common cold, headache, toothache, muscular aches, backache, and minor pain of arthritis.

Dysmenorrhea

Symptomatic management of primary dysmenorrhea.

Self-medication for the temporary relief of minor aches and pain associated with menstrual cramps.

Fever

Self-medication for reduction of fever in adolescents ≥12 years of age and adults.

Naproxen Dosage and Administration

General

  • Consider potential benefits and risks of naproxen therapy as well as alternative therapies before initiating therapy with the drug.

Administration

Oral Administration

Formulation Considerations

Naproxen oral suspension is the preferred dosage form for children because of suitability for providing the calculated dosage. Do not use naproxen tablets in children weighing <50 kg.

Naproxen sodium is preferred for management of acute painful conditions when prompt onset of pain relief is desired.

Naproxen delayed-release preparations are not recommended for management of acute gout, tendinitis, bursitis, acute pain, or dysmenorrhea because of slow onset of action.

Naproxen or Naproxen Sodium Conventional (Immediate-release) Tablets and Naproxen Suspension

Usually administered orally twice daily. When used for the management of osteoarthritis, rheumatoid arthritis, or ankylosing spondylitis, the morning and evening doses may be unequal in size.

Administration with meal, milk, or antacids may minimize adverse GI effects.

Shake oral suspension gently prior to use; to ensure accurate measurement of the dose, always use a calibrated measuring device to administer the oral suspension.

Naproxen Delayed-release Tablets

Usually administered orally twice daily. When used for the management of osteoarthritis, rheumatoid arthritis, or ankylosing spondylitis, the morning and evening doses may be unequal in size.

Do not break, crush, or chew naproxen delayed-release tablets.

Administration with meal, milk, or antacids may minimize adverse GI effects.

Naproxen Sodium Extended-release Tablets

Administer orally once daily.

Administration with meal, milk, or antacids may minimize adverse GI effects.

Tablets Containing Delayed-release Naproxen and Immediate-release Esomeprazole

Administer orally twice daily.

Swallow whole with liquid; do not split, chew, crush, or dissolve tablets.

Administer at least 30 minutes before meals; patient may use antacids during therapy.

Tablets Containing Naproxen Sodium and Sumatriptan

Administer with or without food; do not split, crush, or chew.

Dosage

Available as naproxen or naproxen sodium; 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.

If changing from one strength to another or one dosage form to another, be aware that different dose strengths and formulations are not necessarily bioequivalent.

To minimize the potential risk of adverse cardiovascular and/or GI events, use lowest effective dosage and shortest duration of therapy consistent with the patient’s treatment goals. Adjust dosage based on individual requirements and response; attempt to titrate to the lowest effective dosage.

Pediatric Patients

Inflammatory Diseases
Juvenile Idiopathic Arthritis
Oral

Naproxen 10 mg/kg daily in 2 divided doses.

Tablets containing delayed-release naproxen and immediate-release esomeprazole in adolescents ≥12 years of age: 375 or 500 mg of naproxen twice daily in those weighing ≥50 kg; 375 mg twice daily in those weighing 38 to <50 kg.

Pain
Oral

Naproxen sodium self-medication in adolescents ≥12 years of age: 220 mg every 8–12 hours; may initiate with 440 mg within the first hour and 220 mg 12 hours later.

Dysmenorrhea
Oral

Naproxen sodium self-medication in adolescents ≥12 years of age: 220 mg every 8–12 hours; may initiate with 440 mg within the first hour and 220 mg 12 hours later.

Fever
Oral

Naproxen sodium self-medication in adolescents ≥12 years of age: 220 mg every 8–12 hours; may initiate with 440 mg within the first hour and 220 mg 12 hours later.

Adults

Inflammatory Diseases
Osteoarthritis, Rheumatoid Arthritis, or Ankylosing Spondylitis
Oral

Preparation

Dosage

Naproxen conventional tablets, delayed-release tablets, or suspension

250–500 mg twice daily; may increase dosage to 1.5 g daily for up to 6 months

Naproxen sodium conventional tablets

275–550 mg twice daily; may increase dosage to 1.65 g daily for up to 6 months

Naproxen sodium extended-release tablets

825 mg or 1.1 g once daily; may increase dosage to 1.65 g daily for up to 6 months

Tablets containing delayed-release naproxen and immediate-release esomeprazole

375 or 500 mg of naproxen (with esomeprazole 20 mg) twice daily

Acute Tendinitis/Bursitis
Oral

Preparation

Dosage

Naproxen conventional tablets or suspension

500 mg initially, followed by 500 mg every 12 hours or 250 mg every 6–8 hours as needed

Naproxen sodium conventional tablets

550 mg initially, followed by 550 mg every 12 hours or 275 mg every 6–8 hours as needed

Naproxen sodium extended-release tablets

1.1 g once daily; may increase dosage to 1.65 g once daily for limited period

Gout
Oral

Preparation

Dosage

Naproxen conventional tablets or suspension

750 mg initially, followed by 250 mg every 8 hours until attack subsides

Naproxen sodium conventional tablets

825 mg initially, followed by 275 mg every 8 hours until attack subsides

Naproxen sodium extended-release tablets

1.1–1.65 g once on first day, followed by 1.1 g once daily until attack subsides

Pain
Oral

Preparation

Dosage

Naproxen conventional tablets or suspension

500 mg initially, followed by 500 mg every 12 hours or 250 mg every 6–8 hours as needed

Naproxen sodium conventional tablets

550 mg initially, followed by 550 mg every 12 hours or 275 mg every 6–8 hours as needed

Naproxen sodium extended-release tablets

1.1 g once daily; may increase dosage to 1.65 g once daily for limited period

Naproxen sodium for self-medication of minor aches and pain: 220 mg every 8–12 hours; may initiate with 440 mg within the first hour and 220 mg 12 hours later.

Acute Migraine Attack
Oral

Naproxen sodium/sumatriptan fixed combination: Naproxen sodium 500 mg (with sumatriptan 85 mg) as a single dose. Efficacy of >1 dose not established. If a second dose is administered, allow ≥2 hours to elapse between the first and second doses.

Dysmenorrhea
Oral

Preparation

Dosage

Naproxen conventional tablets or suspension

500 mg initially, followed by 500 mg every 12 hours or 250 mg every 6–8 hours as needed

Naproxen sodium conventional tablets

550 mg initially, followed by 550 mg every 12 hours or 275 mg every 6–8 hours as needed

Naproxen sodium extended-release tablets

1.1 g once daily; may increase dosage to 1.65 g once daily for limited period

Naproxen sodium self-medication: 220 mg every 8–12 hours; may initiate with 440 mg within the first hour and 220 mg 12 hours later.

Fever
Oral

Naproxen sodium self-medication: 220 mg every 8–12 hours; may initiate with 440 mg within the first hour and 220 mg 12 hours later.

Prescribing Limits

Pediatric Patients

Pain
Oral

Naproxen sodium self-medication in adolescents ≥12 years of age: Maximum 440 mg in 8–12 hours; 660 mg in 24 hours. Self-medication should not exceed 10 days.

Dysmenorrhea
Oral

Naproxen sodium self-medication in adolescents ≥12 years of age: Maximum 440 mg in 8–12 hours; 660 mg in 24 hours.

Fever
Oral

Naproxen sodium self-medication in adolescents ≥12 years of age: Maximum 440 mg in 8–12 hours; 660 mg in 24 hours. Self-medication should not exceed 3 days.

Adults

Inflammatory Diseases
Osteoarthritis, Rheumatoid Arthritis, or Ankylosing Spondylitis
Oral

As naproxen, maximum 1.5 g daily.

As naproxen sodium, maximum 1.65 g daily.

Acute Tendinitis/Bursitis
Oral

As naproxen, maximum 1.25 g on the first day; thereafter, 1 g daily. Maximum 1.5 g daily for limited period.

As naproxen sodium, maximum 1.375 g on the first day; thereafter, 1.1 g daily. Maximum 1.65 g daily for limited period.

Pain
Oral

As naproxen, maximum 1.25 g on the first day; thereafter, 1 g daily. Maximum 1.5 g daily for limited period.

As naproxen sodium, maximum 1.375 g on the first day; thereafter, 1.1 g daily. Maximum 1.65 g daily for limited period.

Naproxen sodium for self-medication of minor aches and pain: Maximum 440 mg in 8–12 hours; 660 mg in 24 hours. Self-medication should not exceed 10 days.

Acute Migraine Attack
Oral

Naproxen sodium/sumatriptan fixed combination: Maximum 2 doses (total sumatriptan dosage of 170 mg) in any 24-hour period. Safety of treating an average of >5 headaches per 30-day period not established.

Dysmenorrhea
Oral

As naproxen, maximum 1.25 g on the first day; thereafter, 1 g daily.

As naproxen sodium, maximum 1.375 g on the first day; thereafter, 1.1 g daily.

Naproxen sodium self-medication: Maximum 440 mg in 8–12 hours; 660 mg in 24 hours.

Fever
Oral

Naproxen sodium self-medication: Maximum 440 mg in 8–12 hours; 660 mg in 24 hours. Self-medication should not exceed 3 days.

Special Populations

Hepatic Impairment

Dosage adjustment may be needed if high doses required. Consider reduced initial dosage. Use lowest effective dosage. (See Hepatic Impairment under Cautions.)

Tablets containing delayed-release naproxen and immediate-release esomeprazole not recommended for patients with severe hepatic impairment; an appropriate esomeprazole dosage is not available as a fixed-ratio preparation for twice-daily dosing.

Do not use tablets containing naproxen sodium and sumatriptan in patients with hepatic impairment; sumatriptan dosage cannot be appropriately adjusted.

Renal Impairment

Consider reduced initial dosage. (See Renal Impairment under Cautions.)

Not recommended for use in patients with moderate to severe renal impairment (Clcr <30 mL/minute).

Geriatric Patients

Dosage adjustment may be needed if high doses required. Consider reduced initial dosage. Use lowest effective dosage. (See Geriatric Use under Cautions.)

Cautions for Naproxen

Contraindications

  • Known hypersensitivity (e.g., anaphylaxis, serious dermatologic reactions) to naproxen or any ingredient in the formulation.

  • History of asthma, urticaria, or other sensitivity reaction precipitated by aspirin or other NSAIAs.

  • In the setting of CABG surgery.

Warnings/Precautions

Warnings

Cardiovascular Thrombotic Effects

NSAIAs (selective COX-2 inhibitors, prototypical NSAIAs) increase the risk of serious adverse cardiovascular thrombotic events (e.g., MI, stroke) in patients with or without cardiovascular disease or risk factors for cardiovascular disease.

Findings of FDA review of observational studies, meta-analysis of randomized controlled trials, and other published information indicate that NSAIAs may increase the risk of such events by 10–50% or more, depending on the drugs and dosages studied.

Relative increase in risk appears to be similar in patients with or without known underlying cardiovascular disease or risk factors for cardiovascular disease, but 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.

Increased risk may occur early (within the first weeks) following initiation of therapy and may increase with higher dosages and longer durations of use.

In controlled studies, increased risk of MI and stroke observed in patients receiving a selective COX-2 inhibitor for analgesia in first 10–14 days following CABG surgery.

In patients receiving NSAIAs following MI, increased risk of reinfarction and death observed beginning in the first week of treatment.

Increased 1-year mortality rate observed in patients receiving NSAIAs following MI; absolute mortality rate declined somewhat after the first post-MI year, but the increased relative risk of death persisted over at least the next 4 years.

Some systematic reviews of controlled observational studies and meta-analyses of randomized studies suggest naproxen may be associated with lower risk of cardiovascular thrombotic events compared with other NSAIAs. FDA states that limitations of these studies and indirect comparisons preclude definitive conclusions regarding relative risks of NSAIAs.

Use NSAIAs with caution and careful monitoring (e.g., monitor for development of cardiovascular events throughout therapy, even in those without prior cardiovascular symptoms) and at the lowest effective dosage for the shortest duration necessary.

Some clinicians suggest that it may be prudent to avoid NSAIA use, whenever possible, in patients with cardiovascular disease. Avoid use in patients with recent MI unless benefits of therapy are expected to outweigh risk of recurrent cardiovascular thrombotic events; if used, monitor for cardiac ischemia. Contraindicated in the setting of CABG surgery.

No consistent evidence that concomitant use of low-dose aspirin mitigates the increased risk of serious adverse cardiovascular events associated with NSAIAs. (See Specific Drugs under Interactions.)

GI Effects

Serious, sometimes fatal, GI toxicity (e.g., bleeding, ulceration, or perforation of esophagus, stomach, or small or large intestine) can occur with or without warning symptoms.

Risk for GI bleeding increased more than tenfold in patients with a history of peptic ulcer disease and/or GI bleeding who are receiving NSAIAs compared with patients without these risk factors.

Other risk factors for GI bleeding include concomitant use of oral corticosteroids, anticoagulants, aspirin, or SSRIs; longer duration of NSAIA therapy (however, short-term therapy is not without risk); smoking; alcohol use; older age; poor general health status; and advanced liver disease and/or coagulopathy.

Most spontaneous reports of fatal adverse GI effects involve geriatric or debilitated patients.

Frequency of NSAIA-associated upper GI ulcers, gross bleeding, or perforation is approximately 1% in patients receiving NSAIAs for 3–6 months and 2–4% at one year.

Use at lowest effective dosage for the shortest duration necessary.

Avoid use of more than one NSAIA at a time. (See Specific Drugs under Interactions.)

Avoid use of NSAIAs in patients at higher risk for GI toxicity unless expected benefits outweigh increased risk of bleeding; consider alternate therapies in high-risk patients and those with active GI bleeding.

For patients at high risk for complications from NSAIA-induced GI ulceration (e.g., bleeding, perforation), consider concomitant use of misoprostol; alternatively, consider concomitant use of a proton-pump inhibitor (e.g., esomeprazole, omeprazole) or use of an NSAIA that is a selective inhibitor of COX-2 (e.g., celecoxib).

Monitor for GI ulceration and bleeding; even closer monitoring for GI bleeding recommended in those receiving concomitant low-dose aspirin for cardiovascular prophylaxis.

If serious adverse GI event suspected, promptly initiate evaluation and discontinue naproxen until serious adverse GI event ruled out.

Other Warnings and Precautions

Hepatic Effects

Severe, sometimes fatal, reactions including fulminant hepatitis, liver necrosis, and hepatic failure reported rarely with NSAIAs.

Elevations of serum ALT or AST reported.

Monitor liver function periodically during long-term therapy. Monitor for symptoms and/or signs suggesting liver dysfunction; monitor abnormal liver function test results. Discontinue immediately and perform clinical evaluation if signs or symptoms of liver disease or systemic manifestations (e.g., eosinophilia, rash) occur.

Hypertension

Hypertension and worsening of preexisting hypertension reported; either event may contribute to the increased incidence of cardiovascular events. Monitor BP during initiation of naproxen and throughout therapy.

Impaired response to ACE inhibitors, angiotensin II receptor antagonists, β-blockers, and certain diuretics may occur. (See Specific Drugs under Interactions.)

Heart Failure and Edema

Fluid retention and edema reported.

NSAIAs (selective COX-2 inhibitors, prototypical NSAIAs) may increase morbidity and mortality in patients with heart failure.

NSAIAs may diminish cardiovascular effects of diuretics, ACE inhibitors, or angiotensin II receptor antagonists used to treat heart failure or edema. (See Specific Drugs under Interactions.)

Manufacturer recommends avoiding use in patients with severe heart failure unless benefits of therapy are expected to outweigh risk of worsening heart failure; if used, monitor for worsening heart failure.

Some experts recommend avoiding use, whenever possible, in patients with reduced left ventricular ejection fraction and current or prior symptoms of heart failure.

Sodium Content

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; each mL of naproxen suspension contains about 0.3 mEq of sodium. Caution in patients with fluid retention, hypertension, or heart failure.

Renal Effects

Direct renal injury, including renal papillary necrosis, reported in patients receiving long-term NSAIA therapy.

Potential for overt renal decompensation. Increased risk of renal toxicity in patients with renal or hepatic impairment or heart failure, in patients with volume depletion, in geriatric patients, and in those receiving a diuretic, ACE inhibitor, or angiotensin II receptor antagonist. (See Renal Impairment under Cautions.)

Correct fluid depletion before initiating naproxen therapy; monitor renal function during therapy in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia.

Hyperkalemia

Hyperkalemia reported with NSAIAs, even in some patients without renal impairment; in such patients, effects attributed to a hyporenin-hypoaldosterone state.

Hypersensitivity Reactions

Anaphylactic reactions reported. Immediate medical intervention and discontinuance for anaphylaxis.

Avoid in patients with aspirin triad (aspirin sensitivity, asthma, nasal polyps); in patients with asthma but without known aspirin sensitivity, monitor for changes in manifestations of asthma.

Potentially fatal or life-threatening syndrome of multi-organ hypersensitivity (i.e., drug reaction with eosinophilia and systemic symptoms [DRESS]) reported in patients receiving NSAIAs. Clinical presentation is variable, but typically includes eosinophilia, fever, rash, lymphadenopathy, and/or facial swelling, possibly associated with other organ system involvement (e.g., hepatitis, nephritis, hematologic abnormalities, myocarditis, myositis). Symptoms may resemble those of acute viral infection. Early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present in the absence of rash. If signs or symptoms of DRESS develop, discontinue naproxen and immediately evaluate the patient.

Dermatologic Reactions

Serious skin reactions (e.g., exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis) reported; can occur without warning. Discontinue at first appearance of rash or any other sign of hypersensitivity (e.g., blisters, fever, pruritus).

Hematologic Effects

Anemia reported rarely. May be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. Periodically determine hemoglobin concentrations during long-term therapy in patients with initial values ≤10 g/dL. Determine hemoglobin concentration or hematocrit in patients receiving long-term therapy if signs or symptoms of anemia occur.

NSAIAs may increase risk of bleeding. Patients with certain coexisting conditions (e.g., coagulation disorders) or receiving concomitant therapy with anticoagulants, antiplatelet agents, or serotonin-reuptake inhibitors may be at increased risk; monitor such patients for bleeding. (See Specific Drugs under Interactions.)

May inhibit platelet aggregation and prolong bleeding time.

Ocular Effects

Visual disturbances reported; ophthalmic evaluation recommended if visual changes occur.

Use of Fixed Combinations

When used in fixed combination with other agents, consider the cautions, precautions, and contraindications associated with the concomitant agents.

Concomitant NSAIA Therapy

Concomitant use with other NSAIAs not recommended. (See Specific Drugs under Interactions.) Do not use multiple naproxen-containing preparations concomitantly.

Other Precautions

May mask certain signs of infection.

Obtain CBC and chemistry profile periodically during long-term use.

Specific Populations

Pregnancy

Use of NSAIAs during pregnancy at about ≥30 weeks’ gestation can cause premature closure of the fetal ductus arteriosus; use at about ≥20 weeks’ gestation associated with fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment.

Effects of NSAIAs on the human fetus during 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.

Avoid use of NSAIAs in pregnant women at about ≥30 weeks’ gestation; if use required between about 20 and 30 weeks’ gestation, use lowest effective dosage and shortest possible duration of treatment, and consider monitoring amniotic fluid volume via ultrasound examination if treatment duration >48 hours; if oligohydramnios occurs, discontinue drug and follow up according to clinical practice. (See Advice to Patients.)

Fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment observed, on average, following days to weeks of maternal NSAIA use; infrequently, oligohydramnios observed as early as 48 hours after initiation of NSAIAs. Oligohydramnios is often, but not always, reversible (generally within 3–6 days) following NSAIA discontinuance. Complications of prolonged oligohydramnios may include limb contracture and delayed lung maturation. In limited number of cases, neonatal renal dysfunction (sometimes irreversible) occurred without oligohydramnios. Some neonates have required invasive procedures (e.g., exchange transfusion, dialysis). Deaths associated with neonatal renal failure also reported. Limitations of available data (lack of control group; limited information regarding dosage, duration, and timing of drug exposure; concomitant use of other drugs) preclude a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAIA use. Available data on neonatal outcomes generally involved preterm infants; extent to which risks can be generalized to full-term infants is uncertain.

Animal data indicate important roles for prostaglandins in kidney development and endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, inhibitors of prostaglandin synthesis increased pre- and post-implantation losses; also impaired kidney development at clinically relevant doses.

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

Lactation

Distributed into milk (concentration approximately 1% of peak plasma concentration).

Consider developmental and health benefits of breast-feeding along with the mother’s clinical need for naproxen and any potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.

Fertility

NSAIAs may be associated with reversible infertility in some women. Reversible delays in ovulation observed in limited studies in women receiving NSAIAs; animal studies indicate that inhibitors of prostaglandin synthesis can disrupt prostaglandin-mediated follicular rupture required for ovulation.

Consider withdrawal of NSAIAs in women experiencing difficulty conceiving or undergoing evaluation of infertility.

Pediatric Use

Safety and efficacy not established in children <2 years of age.

Should not be used for self-medication in children <12 years of age unless otherwise directed by a clinician.

Dosing recommendations for juvenile idiopathic arthritis based on well-controlled studies.

Safety of extended-release naproxen sodium tablets not established in children.

Risk of overdosage and toxicity (including death) in children <2 years of age receiving OTC preparations containing antihistamines, cough suppressants, expectorants, and nasal decongestants alone or in combination for relief of symptoms of upper respiratory tract infection. Such preparations also may contain analgesics and antipyretics. Limited evidence of efficacy for these preparations in this age group; appropriate dosages not established. Therefore, FDA recommended not to use such preparations in children <2 years of age; safety and efficacy in older children currently under evaluation. 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 agreed to voluntarily revise the product labeling to state that such preparations should not be used in children <4 years of age. FDA recommends that parents and caregivers adhere to dosage instructions and warnings on the product labeling that accompanies the preparation and consult a clinician about any concerns.

Geriatric Use

Increased risk for serious adverse cardiovascular, GI, and renal effects. Geriatric patients appear to tolerate GI ulceration and bleeding less well than other individuals. Fatal adverse GI effects reported more frequently in geriatric patients than younger adults. If anticipated benefits outweigh potential risks, initiate at lower end of dosing range and monitor for adverse effects.

Increase in unbound naproxen concentrations in geriatric patients could be associated with increased frequency of adverse events at any given dosage. (See Distribution: Special Populations, under Pharmacokinetics.)

Consider lower dosage. Select dosage with caution because of age-related decreases in renal function. May be useful to monitor renal function.

Caution advised if high dosages required.

Hepatic Impairment

Not evaluated in patients with hepatic impairment.

Consider lower dosage.

Caution advised if high dosages required. (See Distribution: Special Populations, under Pharmacokinetics.)

Renal Impairment

Not evaluated in patients with renal impairment.

Consider lower dosage.

May hasten progression of renal dysfunction in patients with preexisting renal disease. Monitor patients with preexisting renal disease for worsening renal function.

Avoid use in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function. Use not recommended in patients with moderate to severe renal impairment; close monitoring of renal function advised if used.

Naproxen and its metabolites and conjugates eliminated principally via the kidney. (See Elimination: Special Populations, under Pharmacokinetics.)

Common Adverse Effects

Abdominal pain, dyspepsia, edema, ecchymoses, flu-like syndrome, headache, nausea, rash.

Interactions for Naproxen

Extensively metabolized by CYP1A2 and CYP2C9. Does not induce drug-metabolizing enzymes.

Protein-bound Drugs

Pharmacokinetic interaction possible; caution advised. Observe for adverse effects if used with other protein-bound drugs. Adjust dosage as needed.

Specific Drugs

Drug

Interaction

Comments

ACE inhibitors

Reduced BP response to ACE inhibitor

Possible deterioration of renal function, including acute renal failure, in geriatric patients and patients with volume depletion or renal impairment

Monitor BP

Ensure adequate hydration; assess renal function when initiating concomitant therapy and periodically thereafter

Monitor geriatric patients and patients with volume depletion or renal impairment for worsening renal function

Alcohol

Increased risk of GI bleeding

Angiotensin II receptor antagonists

Reduced BP response to angiotensin II receptor antagonist

Possible deterioration of renal function, including acute renal failure, in geriatric patients and patients with volume depletion or renal impairment

Monitor BP

Ensure adequate hydration; assess renal function when initiating concomitant therapy and periodically thereafter

Monitor geriatric patients and patients with volume depletion or renal impairment for worsening renal function

Antacids

Possible delayed absorption of naproxen

Concomitant administration not recommended

Anticoagulants (e.g., warfarin)

Possible bleeding complications

Higher risk of GI bleeding compared with either agent alone

Carefully observe for signs of bleeding

β-Adrenergic blocking agents

Reduced BP response

Monitor BP

Cholestyramine

Delayed absorption of naproxen

Concomitant administration not recommended

Cimetidine

No change in pharmacokinetics of either drug; no change in gastric acid antisecretory effect of cimetidine

Cyclosporine

Possible increase in nephrotoxic effects of cyclosporine

Monitor for worsening renal function

Digoxin

Increased serum concentrations and prolonged half-life of digoxin

Monitor serum digoxin concentrations

Diuretics (furosemide, thiazides)

Reduced natriuretic effects and increased risk of NSAIA-associated nephrotoxicity in dehydrated patients

Monitor for worsening renal function and for adequacy of diuretic and antihypertensive effects

Lithium

Increased plasma lithium concentrations

Monitor for lithium toxicity; adjust lithium dosage as needed

Methotrexate

Possible increased risk of methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction)

Monitor for methotrexate toxicity

NSAIAs

Increased risk of GI ulceration and other complications

Concomitant NSAIAs and aspirin (analgesic dosages): Therapeutic effect not greater than that of NSAIAs alone

No consistent evidence that low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs

Protein binding of NSAIAs reduced by aspirin, but clearance of unbound drug not altered; clinical importance unknown

Concomitant administration may interfere with the antiplatelet effect of low-dose aspirin

Possible increased risk of cardiovascular events following naproxen discontinuance; in one study, naproxen sodium (220 mg once or twice daily) interference with the antiplatelet effect of low-dose, immediate-release aspirin was most marked during washout period following naproxen discontinuance; interaction was greater when naproxen was administered 30 minutes prior to aspirin and minimal when aspirin was administered 30 minutes prior to naproxen; similar interaction possible with higher naproxen dosages and enteric-coated, low-dose aspirin, but timing of peak interference may occur later

Concomitant use with analgesic dosages of aspirin or with other NSAIAs generally not recommended

Advise patients not to take low-dose aspirin without consulting clinician; closely monitor patients receiving concomitant antiplatelet agents (e.g., aspirin) and NSAIAs for bleeding

Not a substitute for low-dose aspirin

Consider an alternative NSAIA that does not interfere with the antiplatelet effect of aspirin or a non-NSAIA analgesic for intermittent analgesic therapy in patients receiving low-dose aspirin

Pemetrexed

Possible increased risk of pemetrexed-associated myelosuppression, renal toxicity, and GI toxicity

Short half-life NSAIAs (e. g., diclofenac, indomethacin): Avoid administration beginning 2 days before and continuing through 2 days after pemetrexed administration

Longer half-life NSAIAs (e.g., meloxicam, nabumetone): In the absence of data, avoid administration beginning at least 5 days before and continuing through 2 days after pemetrexed administration

Patients with Clcr 45–79 mL/minute: Monitor for myelosuppression, renal toxicity, and GI toxicity

Probenecid

Increased plasma concentrations and half-life of naproxen

Monitor patient; adjust dosage as needed

Serotonin-reuptake inhibitors (e.g., SSRIs, SNRIs)

Possible increased risk of bleeding due to importance of serotonin release by platelets in hemostasis

Monitor for bleeding

Sucralfate

Delayed absorption of naproxen

Concomitant administration not recommended

Tolbutamide

No change in hypoglycemic effect of tolbutamide

Naproxen Pharmacokinetics

Absorption

Bioavailability

Well absorbed following oral administration; bioavailability is about 95%.

Extent of absorption similar for commercially available formulations; peak plasma concentrations also similar, although about 36% lower with conventional tablets containing naproxen sodium 500 mg and sumatriptan than with conventional naproxen sodium 550-mg tablets.

Rate of absorption varies depending on formulation used. Peak plasma concentration usually attained within about 1–2 hours (naproxen sodium conventional tablets), 2–4 hours (naproxen conventional tablets), 1–4 hours (naproxen suspension), 3 hours (tablets containing delayed-release naproxen and immediate-release esomeprazole), 3–5 hours (naproxen sodium extended-release tablets), 5 hours (conventional tablets containing naproxen sodium and sumatriptan), or 4–6 hours (naproxen delayed-release tablets).

Onset

Naproxen sodium conventional tablets and extended-release tablets provide pain relief within 30 minutes; naproxen conventional tablets provide pain relief within 1 hour.

Duration

Analgesic effect lasts up to 12 hours.

Food

Food delays time to peak plasma concentration by about 6–8 hours following administration as naproxen delayed-release tablets.

High-fat meal delays time to peak plasma naproxen concentration by 10 hours and decreases peak plasma naproxen concentration by about 12% following administration as tablets containing delayed-release naproxen and immediate-release esomeprazole.

Food does not substantially affect bioavailability of naproxen from naproxen sodium/sumatriptan tablets.

Distribution

Plasma Protein Binding

>99%.

Special Populations

Chronic alcoholic liver disease: Total naproxen concentrations are decreased, but concentrations of unbound drug are increased.

Geriatric individuals: Total naproxen concentrations are unchanged, but concentrations of unbound drug are increased. Trough concentration of unbound naproxen is 0.12–0.19% of total naproxen concentration, compared with 0.05–0.075% in younger individuals.

Elimination

Metabolism

Extensively metabolized in the liver by CYP1A2 and CYP2C9 to 6-desmethylnaproxen.

Elimination Route

Excreted in urine (95%) mainly as conjugates of naproxen or 6-desmethylnaproxen.

Half-life

12–17 hours.

Special Populations

Renal impairment: Possible accumulation of naproxen metabolites. Naproxen elimination decreased in patients with severe renal impairment.

Stability

Storage

Oral

Conventional and Delayed-release Tablets

15–30°C.

Extended-release Tablets

20–25°C (may be exposed to 15–30°C).

Tablets Containing Delayed-release Naproxen and Immediate-release Esomeprazole

25°C (may be exposed to 15–30°C); protect from moisture.

Tablets Containing Naproxen Sodium and Sumatriptan

25°C (may be exposed to 15–30°C). Store in original container with desiccant packet; do not repackage.

Suspension

20–25°C in light-resistant container (may be exposed to 15–30°C); avoid temperatures >40°C.

Actions

  • Inhibits cyclooxygenase-1 (COX-1) and COX-2.

  • Pharmacologic actions similar to those of other prototypical NSAIAs; exhibits anti-inflammatory, analgesic, and antipyretic activity.

Advice to Patients

  • Importance of reading the medication guide for NSAIAs that is provided each time the drug is dispensed.

  • When used for self-medication, importance of reading the product labeling.

  • When used for self-medication, importance of using the lowest effective dosage and of not exceeding the recommended dosage or duration of therapy.

  • When used for self-medication, importance of reviewing the warning information provided by the manufacturer.

  • Risk of serious cardiovascular events (e.g., MI, stroke). Importance of seeking immediate medical attention if signs and symptoms of a cardiovascular event (chest pain, dyspnea, weakness, slurred speech) occur.

  • Risk of GI bleeding and ulceration. Importance of notifying clinician if signs and symptoms of GI ulceration or bleeding develop. Inform patients receiving concomitant low-dose aspirin of increased risk of GI bleeding.

  • Risk of serious skin reactions, DRESS, and anaphylactic and other sensitivity reactions. Advise patients to stop taking naproxen immediately if they develop any type of rash or fever and to promptly contact their clinician. Importance of seeking immediate medical attention if an anaphylactic reaction occurs.

  • Risk of hepatotoxicity. Importance of discontinuing therapy and contacting clinician immediately if signs and symptoms of hepatotoxicity (nausea, fatigue, lethargy, pruritus, jaundice, upper right quadrant tenderness, flu-like symptoms) occur.

  • Risk of heart failure or edema; importance of reporting dyspnea, unexplained weight gain, or edema.

  • Potential for naproxen to interfere with antiplatelet effect of low-dose aspirin. Importance of consulting clinician prior to taking low-dose aspirin concomitantly.

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

  • Importance of avoiding NSAIA use beginning at 20 weeks’ gestation unless otherwise advised by a clinician; importance of avoiding NSAIAs beginning at 30 weeks’ gestation because of risk of premature closure of the fetal ductus arteriosus; monitoring for oligohydramnios may be necessary if NSAIA therapy required for >48 hours’ duration between about 20 and 30 weeks’ gestation.

  • Advise women who are trying to conceive that NSAIAs may be associated with a reversible delay in ovulation.

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Naproxen

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Suspension

125 mg/5 mL*

Naprosyn

Athena

Naproxen Suspension

Tablets

250 mg*

Naproxen Tablets

375 mg*

Naproxen Tablets

500 mg*

Naprosyn

Canton

Naproxen Tablets

Tablets, delayed-release (enteric-coated)

375 mg*

EC-Naprosyn

Canton

Naproxen Delayed-release Tablets

500 mg*

EC-Naprosyn (scored)

Canton

Naproxen Delayed-release Tablets

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Naproxen Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, delayed-release core (naproxen only)

375 mg with Esomeprazole Magnesium 20 mg (of esomeprazole)*

Naproxen and Esomeprazole Magnesium Delayed-release Tablets

Vimovo

Horizon

500 mg with Esomeprazole Magnesium 20 mg (of esomeprazole)*

Naproxen and Esomeprazole Magnesium Delayed-release Tablets

Vimovo

Horizon

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Naproxen Sodium

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules, liquid-filled

220 mg (equivalent to naproxen 200 mg)*

Aleve

Bayer

Naproxen Sodium Capsules

Tablets

220 mg (equivalent to naproxen 200 mg)*

Aleve

Bayer

Naproxen Sodium Tablets

Tablets, extended-release

412.5 mg (equivalent to 375 mg naproxen)*

Naprelan

Almatica

Naproxen Sodium Extended-release Tablets

550 mg (equivalent to 500 mg naproxen)*

Naprelan

Almatica

Naproxen Sodium Extended-release Tablets

825 mg (equivalent to 750 mg naproxen)*

Naprelan

Almatica

Naproxen Sodium Extended-release Tablets

Tablets, film-coated

275 mg (equivalent to naproxen 250 mg)*

Naproxen Sodium Film-coated Tablets

550 mg (equivalent to naproxen 500 mg)*

Anaprox DS (scored)

Canton

Naproxen Sodium Film-coated Tablets

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Naproxen Sodium Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

220 mg (equivalent to 200 mg naproxen) with Diphenhydramine Hydrochloride 25 mg*

Aleve PM

Bayer

Naproxen Sodium and Diphenhydramine Hydrochloride Tablets

Tablets, film-coated

500 mg (equivalent to 455 mg naproxen) with Sumatriptan Succinate 85 mg (of sumatriptan)*

Sumatriptan and Naproxen Sodium Film-coated Tablets

Treximet

Currax

Naproxen sodium also is commercially available in combination with decongestants.

AHFS DI Essentials™. © Copyright 2021, Selected Revisions October 18, 2021. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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