Brand names: Aleve, Anaprox, Naprelan, Naprosyn
Drug class: Other Nonsteroidal Anti-inflammatory Agents
CAS number: 22204-53-1

Medically reviewed by Drugs.com on Oct 9, 2023. Written by ASHP.

Introduction

Prototypical NSAIA; propionic acid derivative.^{225 230}

Uses for Naproxen

Consider potential benefits and risks of naproxen therapy as well as alternative therapies before initiating therapy with the drug.²²⁵ Use lowest effective dosage and shortest duration of therapy consistent with the patient’s treatment goals.²²⁵

Inflammatory Diseases

Symptomatic treatment of osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis.^{59 104 202 204 205 206 225 230 269} May be used in fixed combination with esomeprazole in patients at risk of developing gastric ulcers associated with NSAIA therapy.²⁶⁷

Symptomatic treatment of tendinitis, bursitis, and acute gout.^{225 230 269}

Management of juvenile idiopathic arthritis in children ≥2 years of age.^{225 269} 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.²⁶⁷

Pain

Relief of pain.^{225 230 269}

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.¹⁰⁵

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.²⁰⁰

Dysmenorrhea

Symptomatic management of primary dysmenorrhea.^{225 230 269}

Self-medication for the temporary relief of minor aches and pain associated with menstrual cramps.²⁰⁰

Fever

Self-medication for reduction of fever in adolescents ≥12 years of age and adults.²⁰⁰

Related/similar drugs

Cimzia, gabapentin, acetaminophen, prednisone, ibuprofen, aspirin, meloxicam

Naproxen Dosage and Administration

General

• Consider potential benefits and risks of naproxen therapy as well as alternative therapies before initiating therapy with the drug.^{225 269}

Administration

Oral Administration

Formulation Considerations

Naproxen oral suspension is the preferred dosage form for children because of suitability for providing the calculated dosage.^{208 225} Do not use naproxen tablets in children weighing <50 kg.^{225 271}

Naproxen sodium is preferred for management of acute painful conditions when prompt onset of pain relief is desired.²²⁵

Naproxen delayed-release preparations are not recommended for management of acute gout, tendinitis, bursitis, acute pain, or dysmenorrhea because of slow onset of action.^{225 267}

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

Usually administered orally twice daily.²²⁵ When used for the management of osteoarthritis, rheumatoid arthritis, or ankylosing spondylitis, the morning and evening doses may be unequal in size.²²⁵

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

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.²⁶⁹

Naproxen Delayed-release Tablets

Usually administered orally twice daily.²²⁵ When used for the management of osteoarthritis, rheumatoid arthritis, or ankylosing spondylitis, the morning and evening doses may be unequal in size.²²⁵

Do not break, crush, or chew naproxen delayed-release tablets.²²⁵

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

Naproxen Sodium Extended-release Tablets

Administer orally once daily.²³⁰

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

Tablets Containing Delayed-release Naproxen and Immediate-release Esomeprazole

Administer orally twice daily.²⁶⁷

Swallow whole with liquid; do not split, chew, crush, or dissolve tablets.²⁶⁷

Administer at least 30 minutes before meals; patient may use antacids during therapy.²⁶⁷

Tablets Containing Naproxen Sodium and Sumatriptan

Administer with or without food; do not split, crush, or chew.²⁶⁸

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.^{200 225 230}

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.²²⁵

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.²²⁵ Adjust dosage based on individual requirements and response; attempt to titrate to the lowest effective dosage.²²⁵

Pediatric Patients

Inflammatory Diseases

Juvenile Idiopathic Arthritis

Oral

Naproxen 10 mg/kg daily in 2 divided doses.^{104 204 205 225 269}

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.²⁶⁷

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.²⁰⁰

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.²⁰⁰

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.²⁰⁰

Adults

Inflammatory Diseases

Osteoarthritis, Rheumatoid Arthritis, or Ankylosing Spondylitis

Oral

Acute Tendinitis/Bursitis

Oral

Gout

Oral

Pain

Oral

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.²⁰⁰

Acute Migraine Attack

Oral

Naproxen sodium/sumatriptan fixed combination: Naproxen sodium 500 mg (with sumatriptan 85 mg) as a single dose.²⁶⁸ Efficacy of >1 dose not established.²⁶⁸ If a second dose is administered, allow ≥2 hours to elapse between the first and second doses.²⁶⁸

Dysmenorrhea

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.²⁰⁰

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.²⁰⁰

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.²⁰⁰ Self-medication should not exceed 10 days.²⁰⁰

Dysmenorrhea

Oral

Naproxen sodium self-medication in adolescents ≥12 years of age: Maximum 440 mg in 8–12 hours; 660 mg in 24 hours.²⁰⁰

Fever

Oral

Naproxen sodium self-medication in adolescents ≥12 years of age: Maximum 440 mg in 8–12 hours; 660 mg in 24 hours.²⁰⁰ Self-medication should not exceed 3 days.²⁰⁰

Adults

Inflammatory Diseases

Osteoarthritis, Rheumatoid Arthritis, or Ankylosing Spondylitis

Oral

As naproxen, maximum 1.5 g daily.²²⁵

As naproxen sodium, maximum 1.65 g daily.²³⁰

Acute Tendinitis/Bursitis

Oral

As naproxen, maximum 1.25 g on the first day; thereafter, 1 g daily.²²⁵ Maximum 1.5 g daily for limited period.²³⁰

As naproxen sodium, maximum 1.375 g on the first day; thereafter, 1.1 g daily.²²⁵ Maximum 1.65 g daily for limited period.²³⁰

Pain

Oral

As naproxen, maximum 1.25 g on the first day; thereafter, 1 g daily.²²⁵ Maximum 1.5 g daily for limited period.²³⁰

As naproxen sodium, maximum 1.375 g on the first day; thereafter, 1.1 g daily.²²⁵ Maximum 1.65 g daily for limited period.²³⁰

Naproxen sodium for self-medication of minor aches and pain: Maximum 440 mg in 8–12 hours; 660 mg in 24 hours.²⁰⁰ Self-medication should not exceed 10 days.²⁰⁰

Acute Migraine Attack

Oral

Naproxen sodium/sumatriptan fixed combination: Maximum 2 doses (total sumatriptan dosage of 170 mg) in any 24-hour period.²⁶⁸ Safety of treating an average of >5 headaches per 30-day period not established.²⁶⁸

Dysmenorrhea

Oral

As naproxen, maximum 1.25 g on the first day; thereafter, 1 g daily.²²⁵

As naproxen sodium, maximum 1.375 g on the first day; thereafter, 1.1 g daily.²²⁵

Naproxen sodium self-medication: Maximum 440 mg in 8–12 hours; 660 mg in 24 hours.²⁰⁰

Fever

Oral

Naproxen sodium self-medication: Maximum 440 mg in 8–12 hours; 660 mg in 24 hours.²⁰⁰ Self-medication should not exceed 3 days.²⁰⁰

Special Populations

Hepatic Impairment

Dosage adjustment may be needed if high doses required.²²⁵ Consider reduced initial dosage.²³⁰ Use lowest effective dosage.²²⁵ (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.²⁶⁷

Do not use tablets containing naproxen sodium and sumatriptan in patients with hepatic impairment; sumatriptan dosage cannot be appropriately adjusted.²⁶⁸

Renal Impairment

Consider reduced initial dosage.²³⁰ (See Renal Impairment under Cautions.)

Not recommended for use in patients with moderate to severe renal impairment (Cl_cr <30 mL/minute).^{225 267}

Geriatric Patients

Dosage adjustment may be needed if high doses required.²²⁵ Consider reduced initial dosage.²³⁰ Use lowest effective dosage.²²⁵ (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.^{225 230}

• History of asthma, urticaria, or other sensitivity reaction precipitated by aspirin or other NSAIAs.^{225 230}

• In the setting of CABG surgery.²²⁵

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.^{225 500 502}

Findings of FDA review of observational studies, meta-analysis of randomized controlled trials, and other published information^{500 501 502} indicate that NSAIAs may increase the risk of such events by 10–50% or more, depending on the drugs and dosages studied.⁵⁰⁰

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.^{225 500 502 506}

Increased 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}

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.²²⁵

In patients receiving NSAIAs following MI, increased risk of reinfarction and death observed beginning in the first week of treatment.^{225 505}

Increased 1-year mortality rate observed in patients receiving NSAIAs following MI;^{225 500 511} 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.^{225 511}

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.^{258 259 260 264 500 501 502 503 506} FDA states that limitations of these studies and indirect comparisons preclude definitive conclusions regarding relative risks of NSAIAs.⁵⁰⁰

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.^{225 500}

Some clinicians suggest that it may be prudent to avoid NSAIA use, whenever possible, in patients with cardiovascular disease.^{505 511 512 516} 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.²²⁵ Contraindicated in the setting of CABG surgery.²²⁵

No consistent evidence that concomitant use of low-dose aspirin mitigates the increased risk of serious adverse cardiovascular events associated with NSAIAs.^{225 502} (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.^{209 210 214 225 230}

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.^{208 225 238}

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.^{208 225 238}

Most spontaneous reports of fatal adverse GI effects involve geriatric or debilitated patients.²²⁵

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.^{209 210 225}

Use at lowest effective dosage for the shortest duration necessary.²²⁵

Avoid use of more than one NSAIA at a time.²²⁵ (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.²²⁵

For patients at high risk for complications from NSAIA-induced GI ulceration (e.g., bleeding, perforation), consider concomitant use of misoprostol;^{212 238 239 240} alternatively, consider concomitant use of a proton-pump inhibitor (e.g., esomeprazole, omeprazole)^{212 238 239} or use of an NSAIA that is a selective inhibitor of COX-2 (e.g., celecoxib).²³⁹

Monitor for GI ulceration and bleeding; even closer monitoring for GI bleeding recommended in those receiving concomitant low-dose aspirin for cardiovascular prophylaxis.²²⁵

If serious adverse GI event suspected, promptly initiate evaluation and discontinue naproxen until serious adverse GI event ruled out.²²⁵

Other Warnings and Precautions

Hepatic Effects

Severe, sometimes fatal, reactions including fulminant hepatitis, liver necrosis, and hepatic failure reported rarely with NSAIAs.^{225 230}

Elevations of serum ALT or AST reported.^{225 230}

Monitor liver function periodically during long-term therapy.^a Monitor for symptoms and/or signs suggesting liver dysfunction; monitor abnormal liver function test results.^{225 230} Discontinue immediately and perform clinical evaluation if signs or symptoms of liver disease or systemic manifestations (e.g., eosinophilia, rash) occur.^{225 230}

Hypertension

Hypertension and worsening of preexisting hypertension reported; either event may contribute to the increased incidence of cardiovascular events.²²⁵ Monitor BP during initiation of naproxen and throughout therapy.²²⁵

Impaired response to ACE inhibitors, angiotensin II receptor antagonists, β-blockers, and certain diuretics may occur.²²⁵ (See Specific Drugs under Interactions.)

Heart Failure and Edema

Fluid retention and edema reported.²²⁵

NSAIAs (selective COX-2 inhibitors, prototypical NSAIAs) may increase morbidity and mortality in patients with heart failure.^{225 500 501 504 507}

NSAIAs may diminish cardiovascular effects of diuretics, ACE inhibitors, or angiotensin II receptor antagonists used to treat heart failure or edema.²²⁵ (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.²²⁵

Some experts recommend avoiding use, whenever possible, in patients with reduced left ventricular ejection fraction and current or prior symptoms of heart failure.⁵⁰⁷

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.^{225 230} Caution in patients with fluid retention, hypertension, or heart failure.^{225 230 269}

Renal Effects

Direct renal injury, including renal papillary necrosis, reported in patients receiving long-term NSAIA therapy.²²⁵

Potential for overt renal decompensation.^{225 230} 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.^{225 230} (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.²²⁵

Hyperkalemia

Hyperkalemia reported with NSAIAs, even in some patients without renal impairment; in such patients, effects attributed to a hyporenin-hypoaldosterone state.²²⁵

Hypersensitivity Reactions

Anaphylactic reactions reported.^{200 225} Immediate medical intervention and discontinuance for anaphylaxis.^{225 230}

Avoid in patients with aspirin triad (aspirin sensitivity, asthma, nasal polyps);^{225 230} in patients with asthma but without known aspirin sensitivity, monitor for changes in manifestations of asthma.^{225 230}

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.²²⁵ 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).²²⁵ Symptoms may resemble those of acute viral infection.²²⁵ Early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present in the absence of rash.²²⁵ If signs or symptoms of DRESS develop, discontinue naproxen and immediately evaluate the patient.²²⁵

Dermatologic Reactions

Serious skin reactions (e.g., exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis) reported; can occur without warning.²²⁵ Discontinue at first appearance of rash or any other sign of hypersensitivity (e.g., blisters, fever, pruritus).²²⁵

Hematologic Effects

Anemia reported rarely.^{225 230} May be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis.²²⁵ Periodically determine hemoglobin concentrations during long-term therapy in patients with initial values ≤10 g/dL.^{225 230} Determine hemoglobin concentration or hematocrit in patients receiving long-term therapy if signs or symptoms of anemia occur.²²⁵

NSAIAs may increase risk of bleeding.²²⁵ 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.²²⁵ (See Specific Drugs under Interactions.)

May inhibit platelet aggregation and prolong bleeding time.^{225 230}

Ocular Effects

Visual disturbances reported; ophthalmic evaluation recommended if visual changes occur.^{225 230}

Use of Fixed Combinations

When used in fixed combination with other agents, consider the cautions, precautions, and contraindications associated with the concomitant agents.^{267 268}

Concomitant NSAIA Therapy

Concomitant use with other NSAIAs not recommended.²²⁵ (See Specific Drugs under Interactions.) Do not use multiple naproxen-containing preparations concomitantly.^{225 230}

Other Precautions

May mask certain signs of infection.^{225 230}

Obtain CBC and chemistry profile periodically during long-term use.²²⁵

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.^{225 1200}

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.¹²⁰²

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.^{225 1200} (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.^{225 1200} Oligohydramnios is often, but not always, reversible (generally within 3–6 days) following NSAIA discontinuance.^{225 1200} Complications of prolonged oligohydramnios may include limb contracture and delayed lung maturation.^{225 1200} In limited number of cases, neonatal renal dysfunction (sometimes irreversible) occurred without oligohydramnios.^{225 1200} Some neonates have required invasive procedures (e.g., exchange transfusion, dialysis).^{225 1200} Deaths associated with neonatal renal failure also reported.¹²⁰⁰ 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.²²⁵ Available data on neonatal outcomes generally involved preterm infants; extent to which risks can be generalized to full-term infants is uncertain.²²⁵

Animal data indicate important roles for prostaglandins in kidney development and endometrial vascular permeability, blastocyst implantation, and decidualization.²²⁵ In animal studies, inhibitors of prostaglandin synthesis increased pre- and post-implantation losses; also impaired kidney development at clinically relevant doses.²²⁵

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

Lactation

Distributed into milk (concentration approximately 1% of peak plasma concentration).^{225 230}

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.²²⁵

Fertility

NSAIAs may be associated with reversible infertility in some women.²²⁵ 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.²²⁵

Consider withdrawal of NSAIAs in women experiencing difficulty conceiving or undergoing evaluation of infertility.²²⁵

Pediatric Use

Safety and efficacy not established in children <2 years of age.²²⁵

Should not be used for self-medication in children <12 years of age unless otherwise directed by a clinician.²⁰⁰

Dosing recommendations for juvenile idiopathic arthritis based on well-controlled studies.²²⁵

Safety of extended-release naproxen sodium tablets not established in children.²³⁰

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.^{265 266} Such preparations also may contain analgesics and antipyretics.²⁶⁵ Limited evidence of efficacy for these preparations in this age group; appropriate dosages not established.²⁶⁵ Therefore, FDA recommended not to use such preparations in children <2 years of age;^b safety and efficacy in older children currently under evaluation.^{d f} 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.^{c d e f} 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.^{c d e}

Geriatric Use

Increased risk for serious adverse cardiovascular, GI, and renal effects.²²⁵ Geriatric patients appear to tolerate GI ulceration and bleeding less well than other individuals.^{225 230} Fatal adverse GI effects reported more frequently in geriatric patients than younger adults.^{225 230} If anticipated benefits outweigh potential risks, initiate at lower end of dosing range and monitor for adverse effects.²²⁵

Increase in unbound naproxen concentrations in geriatric patients could be associated with increased frequency of adverse events at any given dosage.²²⁵ (See Distribution: Special Populations, under Pharmacokinetics.)

Consider lower dosage.²³⁰ Select dosage with caution because of age-related decreases in renal function.^{225 230} May be useful to monitor renal function.^{225 230}

Caution advised if high dosages required.²²⁵

Hepatic Impairment

Not evaluated in patients with hepatic impairment.²²⁵

Consider lower dosage.²³⁰

Caution advised if high dosages required.^{225 230} (See Distribution: Special Populations, under Pharmacokinetics.)

Renal Impairment

Not evaluated in patients with renal impairment.²²⁵

Consider lower dosage.²³⁰

May hasten progression of renal dysfunction in patients with preexisting renal disease.²²⁵ Monitor patients with preexisting renal disease for worsening renal function.²²⁵

Avoid use in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function.²²⁵ Use not recommended in patients with moderate to severe renal impairment; close monitoring of renal function advised if used.²²⁵

Naproxen and its metabolites and conjugates eliminated principally via the kidney.²²⁵ (See Elimination: Special Populations, under Pharmacokinetics.)

Common Adverse Effects

Abdominal pain, dyspepsia, edema, ecchymoses, flu-like syndrome, headache, nausea, rash.^{225 230}

Drug Interactions

Extensively metabolized by CYP1A2 and CYP2C9.²⁶⁷ Does not induce drug-metabolizing enzymes.²²⁵

Protein-bound Drugs

Pharmacokinetic interaction possible; caution advised. Observe for adverse effects if used with other protein-bound drugs.^{225 230} Adjust dosage as needed.^{225 230}

Specific Drugs

Naproxen Pharmacokinetics

Absorption

Bioavailability

Well absorbed following oral administration; bioavailability is about 95%.^{225 230}

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.^{225 267 268 a}

Rate of absorption varies depending on formulation used.^{225 267 268 a} 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).^{225 230 267 268}

Onset

Naproxen sodium conventional tablets and extended-release tablets provide pain relief within 30 minutes; naproxen conventional tablets provide pain relief within 1 hour.^{225 230}

Duration

Analgesic effect lasts up to 12 hours.²²⁵

Food

Food delays time to peak plasma concentration by about 6–8 hours following administration as naproxen delayed-release tablets.²²⁵

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.²⁶⁷

Food does not substantially affect bioavailability of naproxen from naproxen sodium/sumatriptan tablets.²⁶⁸

Distribution

Plasma Protein Binding

>99%.^{225 230}

Special Populations

Chronic alcoholic liver disease: Total naproxen concentrations are decreased, but concentrations of unbound drug are increased.²²⁵

Geriatric individuals: Total naproxen concentrations are unchanged, but concentrations of unbound drug are increased.²²⁵ Trough concentration of unbound naproxen is 0.12–0.19% of total naproxen concentration, compared with 0.05–0.075% in younger individuals.²²⁵

Elimination

Metabolism

Extensively metabolized in the liver by CYP1A2 and CYP2C9 to 6-desmethylnaproxen.^{225 230 267}

Elimination Route

Excreted in urine (95%) mainly as conjugates of naproxen or 6-desmethylnaproxen.^{225 230}

Half-life

12–17 hours.^{225 230 267}

Special Populations

Renal impairment: Possible accumulation of naproxen metabolites.^{225 230} Naproxen elimination decreased in patients with severe renal impairment.²²⁵

Stability

Storage

Oral

Conventional and Delayed-release Tablets

15–30°C.²²⁵

Extended-release Tablets

20–25°C (may be exposed to 15–30°C).²³⁰

Tablets Containing Delayed-release Naproxen and Immediate-release Esomeprazole

25°C (may be exposed to 15–30°C); protect from moisture.²⁶⁷

Tablets Containing Naproxen Sodium and Sumatriptan

25°C (may be exposed to 15–30°C).²⁶⁸ Store in original container with desiccant packet; do not repackage.²⁶⁸

Suspension

20–25°C in light-resistant container (may be exposed to 15–30°C); avoid temperatures >40°C.²⁶⁹

Actions

• Inhibits cyclooxygenase-1 (COX-1) and COX-2.^{231 232 233 234 235 236}

• Pharmacologic actions similar to those of other prototypical NSAIAs; exhibits anti-inflammatory, analgesic, and antipyretic activity.^{225 230}

Advice to Patients

• Importance of reading the medication guide for NSAIAs that is provided each time the drug is dispensed.²²⁵

• When used for self-medication, importance of reading the product labeling.²⁰⁰

• When used for self-medication, importance of using the lowest effective dosage and of not exceeding the recommended dosage or duration of therapy.²⁰⁰

• When used for self-medication, importance of reviewing the warning information provided by the manufacturer.²⁰⁰

• Risk of serious cardiovascular events (e.g., MI, stroke).^{225 500} Importance of seeking immediate medical attention if signs and symptoms of a cardiovascular event (chest pain, dyspnea, weakness, slurred speech) occur.^{225 500}

• Risk of GI bleeding and ulceration.^{225 230} Importance of notifying clinician if signs and symptoms of GI ulceration or bleeding develop.^{225 230} Inform patients receiving concomitant low-dose aspirin of increased risk of GI bleeding.²²⁵

• Risk of serious skin reactions, DRESS, and anaphylactic and other sensitivity reactions.^{225 230} Advise patients to stop taking naproxen immediately if they develop any type of rash or fever and to promptly contact their clinician.²²⁵ Importance of seeking immediate medical attention if an anaphylactic reaction occurs.^{225 230}

• Risk of hepatotoxicity.^{225 230} 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.^{225 230}

• Risk of heart failure or edema; importance of reporting dyspnea, unexplained weight gain, or edema.²²⁵

• Potential for naproxen to interfere with antiplatelet effect of low-dose aspirin.^{200 500} Importance of consulting clinician prior to taking low-dose aspirin concomitantly.²²⁵

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.^{225 230}

• 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.^{225 1200}

• Advise women who are trying to conceive that NSAIAs may be associated with a reversible delay in ovulation.²²⁵

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.^{225 230}

• Importance of informing patients of other important precautionary information.²²⁵ (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

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

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

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

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