Naproxen

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Capsule, Oral, as sodium:

Aleve: 220 mg [contains brilliant blue fcf (fd&c blue #1)]

Generic: 220 mg

Kit, Combination:

Flanax Pain Relief: 500 mg [contains cetearyl alcohol, cremophor el, propylparaben]

Naproxen Comfort Pac: 500 mg [DSC] [contains methylparaben, trolamine (triethanolamine)]

Suspension, Oral:

Naprosyn: 125 mg/5 mL (473 mL) [contains fd&c yellow #6 (sunset yellow), methylparaben, sorbitol; pineapple-orange flavor]

Generic: 125 mg/5 mL (473 mL, 500 mL)

Tablet, Oral:

Naprosyn: 500 mg [DSC] [scored]

Naproxen Kit: 500 mg [DSC]

Generic: 250 mg, 375 mg, 500 mg

Tablet, Oral, as sodium:

Aleve: 220 mg [contains fd&c blue #2 aluminum lake]

All Day Relief: 220 mg [gluten free; contains fd&c blue #2 aluminum lake]

Anaprox DS: 550 mg [DSC] [scored]

CareAll Naproxen: 220 mg [contains corn starch, fd&c blue #2 aluminum lake]

CareAll Naproxen: 220 mg [contains fd&c blue #2 (indigotine)]

Flanax Pain Relief: 220 mg [DSC] [contains fd&c blue #2 (indigotine)]

GoodSense Naproxen Sodium: 220 mg [gluten free; contains fd&c blue #2 aluminum lake]

Mediproxen: 220 mg [contains fd&c blue #2 (indigotine)]

Generic: 220 mg, 275 mg, 550 mg

Tablet Delayed Release, Oral:

EC-Naprosyn: 375 mg, 500 mg [DSC]

EC-Naproxen: 375 mg, 500 mg

Naproxen DR: 375 mg, 500 mg

Tablet Extended Release 24 Hour, Oral, as sodium [strength expressed as base]:

Naprelan: 375 mg, 500 mg, 750 mg

Generic: 375 mg, 500 mg

Pharmacology

Mechanism of Action

Reversibly inhibits cyclooxygenase-1 and 2 (COX-1 and 2) enzymes, which results in decreased formation of prostaglandin precursors; has antipyretic, analgesic, and anti-inflammatory properties

Other proposed mechanisms not fully elucidated (and possibly contributing to the anti-inflammatory effect to varying degrees), include inhibiting chemotaxis, altering lymphocyte activity, inhibiting neutrophil aggregation/activation, and decreasing proinflammatory cytokine levels.

Pharmacokinetics/Pharmacodynamics

Absorption

Oral: Almost 100%

Distribution

0.16 L/kg

Metabolism

Extensively metabolized in the liver to 6-0-desmethyl naproxen; parent drug and desmethyl metabolite undergo further metabolism to their respective acylglucuronide conjugated metabolites

Excretion

Urine (95%; primarily as metabolites); feces (≤3%)

Onset of Action

Analgesic: 30 to 60 minutes

Time to Peak

Serum:

Tablets, naproxen: 2 to 4 hours

Tablets, naproxen sodium: 1 to 2 hours

Tablets, delayed-release (empty stomach): 4 to 6 hours; range: 2 to 12 hours

Tablets, delayed-release (with food): 12 hours; range: 4 to 24 hours

Suspension: 1 to 4 hours

Suppository [Canadian product]: 2 to 3 hours

Duration of Action

Analgesic: <12 hours

Half-Life Elimination

Children: Range: 8 to 17 hours

Children 8 to 14 years: 8 to 10 hours

Adults: Normal renal function: 12 to 17 hours; Moderate-to-severe renal impairment: ~15 to 21 hours (Anttila 1980)

Protein Binding

>99% to albumin; increased free fraction in elderly

Use in Specific Populations

Special Populations: Renal Function Impairment

Metabolites and conjugates may accumulate.

Use: Labeled Indications

Ankylosing spondylitis, bursitis, gout (acute flares), polyarticular juvenile idiopathic arthritis, osteoarthritis, rheumatoid arthritis, tendonitis (Rx products only): Relief of the signs and symptoms of acute flares of gout, ankylosing spondylitis, bursitis, polyarticular juvenile idiopathic arthritis (excluding ER tablets), osteoarthritis, rheumatoid arthritis, and tendonitis. Delayed-release naproxen is not recommended for initial treatment of acute pain.

Pain, primary dysmenorrhea (Rx and OTC products): Relief of mild to moderate pain and the treatment of primary dysmenorrhea. Delayed-release naproxen is not recommended for initial treatment of acute pain.

Use: Off Label

Migraine, acute (treatment)c

Data from two randomized, double-blind, placebo-controlled, crossover studies support the use of naproxen in the treatment of acute migraine Andersson 1989, Nestvold 1985. Additional trials may be necessary to further define the role of naproxen in this condition.

Contraindications

Hypersensitivity to naproxen (eg, anaphylactic reactions, serious skin reactions) or any component of the formulation; history of asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs; use in the setting of coronary artery bypass graft (CABG) surgery

Canadian labeling: Additional contraindications (not in US labeling): Active gastric, duodenal, or peptic ulcers; active GI bleeding; cerebrovascular bleeding or other bleeding disorders; active GI inflammatory disease; severe liver impairment or active liver disease; severe renal impairment (CrCl <30 mL/minute) or deteriorating renal disease; severe uncontrolled heart failure; known hyperkalemia; third trimester of pregnancy; breast-feeding; inflammatory lesions or recent bleeding of the rectum or anus (suppository only); use in patients <16 years of age (suppository only); use in patients <18 years of age (naproxen enteric coated and sustained release tablets and naproxen sodium tablets); use in children <2 years (naproxen tablets and suspension).

Dosage and Administration

Dosing: Adult

Note: Dosage expressed as naproxen base; 200 mg naproxen base is equivalent to 220 mg naproxen sodium. For relief of acute pain, naproxen sodium may be preferred due to more rapid absorption and onset; naproxen base may also be used however EC-Naprosyn is not recommended.

Ankylosing spondylitis, osteoarthritis, rheumatoid arthritis: Oral: 500 to 1,000 mg daily in 2 divided doses; in patients who require higher level of anti-inflammatory/analgesic activity and have tolerated lower doses, may increase to 1,500 mg/day for limited time period (<6 months)

Naproxen extended-release tablets: Initial: 750 to 1,000 mg once daily; in patients who require higher level of anti-inflammatory/analgesic activity and have tolerated lower doses, may temporarily increase to 1,500 mg once daily

Rectal suppository [Canadian product]: Insert one 500 mg suppository into the rectum once daily (Note: Suppository may be used to substitute for one oral dose in patients receiving 1,000 mg naproxen daily).

Gout, acute flares (alternative agent): Oral: 500 mg twice daily (Janssens 2008); initiate within 24 to 48 hours of flare onset preferably; discontinue 2 to 3 days after resolution of clinical signs; usual duration: 5 to 7 days (ACR [Khanna 2012]; Becker 2018)

Manufacturer's labeling: Dosing in the prescribing information may not reflect current clinical practice.

Immediate release: Initial: 750 mg followed by 250 mg every 8 hours

Extended-release tablets: Initial: 1,000 to 1,500 mg once daily followed by 1,000 mg once daily. Note: Naproxen delayed-release tablets are not recommended because of the delay in absorption.

Pain (mild to moderate), dysmenorrhea, acute tendonitis, bursitis: Oral: Initial: 500 mg, followed by 500 mg every 12 hours or 250 mg every 6 to 8 hours; maximum daily dose: Day 1: 1,250 mg; subsequent daily doses should not exceed 1,000 mg

Naproxen extended-release tablets: Oral: Initial: 1,000 mg once daily; may temporarily increase to 1,500 mg once daily if greater pain relief is needed. Dose should be subsequently reduced to a maximum of 1,000 mg daily.

Episodic migraine prevention (off-label use): Oral: 250 to 500 mg twice daily (EFNS [Evers 2009]). Continue treatment for 2 to 3 months to assess clinical benefit; consider tapering or discontinuing dose if headaches are well-controlled after 3 to 6 months (AAN [Silberstein 2000]).

Migraine, acute (off label use): Initial: 750 mg; an additional 250 to 500 mg may be given if needed (maximum: 1,250 mg in 24 hours) (Andersson, 1989; Nestvold, 1985).

OTC labeling: Pain, fever: 200 mg every 8 to 12 hours; if needed, may take 400 mg for the initial dose; maximum: 400 mg in any 8- to 12-hour period or 600 mg/24 hours

Dosing: Geriatric

Use with caution; consider using a reduced dose. Refer to adult dosing.

Dosing: Pediatric

Note: Dosage expressed as naproxen base; 200 mg naproxen base is equivalent to 220 mg naproxen sodium. In pediatric patients, all dosing is for the immediate release preparations.

Analgesia/pain, mild to moderate:

Children and Adolescents <60 kg: Limited data available: Oral: 5 to 6 mg/kg/dose every 12 hours; maximum daily dose: 1,000 mg/day (Berde 2002); doses as high as 10 mg/kg/dose have also been recommended (APS 2008)

Children and Adolescents ≥60 kg: Limited data available: Oral: 250 to 375 mg twice daily; maximum daily dose: 1,000 mg/day (Berde 2002)

OTC labeling: Children ≥12 years and Adolescents: Oral: 200 mg every 8 to 12 hours; if needed may take 400 mg for the initial dose; maximum daily dose: 600 mg/day

Fever: OTC labeling: Children ≥12 years and Adolescents: Oral: 200 mg every 8 to 12 hours; if needed may take 400 mg for the initial dose; maximum daily dose: 600 mg/day

Juvenile idiopathic arthritis: Children and Adolescents: Oral: 10 to 15 mg/kg/day in 2 divided doses; Maximum daily dose: 1,000 mg/day (Hollingsworth 1993; Kliegman 2016; Litalien 2001)

Ankylosing spondylitis: Limited data available: Children and Adolescents: Oral: 15 to 20 mg/kg/day in 2 divided doses; maximum daily dose: 1,500 mg/day; adult dosing suggests limiting this maximum daily dose to <6 months of therapy (APS 2008; Kliegman 2016)

Administration

Oral: Administer with food, milk, or antacids to decrease GI adverse effects.

Suspension: Shake suspension well before administration.

Tablet, delayed or extended release: Swallow tablet whole; do not break, crush, or chew.

Rectal suppository [Canadian product]: Insert suppository into rectum.

Dietary Considerations

Sodium content: Naproxen sodium products contain about 50 mg (2 mEq) of sodium per 500 mg of naproxen. Naprosyn suspension contains 39 mg of sodium per 5 mL (125 mg). Consider this in patients whose overall intake of sodium must be severely restricted.

Storage

Store at 15°C to 30°C (59°F to 86°F); suspension should not be exposed to excessive heat (>40°C [104°F]).

Drug Interactions

5-Aminosalicylic Acid Derivatives: Nonsteroidal Anti-Inflammatory Agents may enhance the nephrotoxic effect of 5-Aminosalicylic Acid Derivatives. Monitor therapy

Acalabrutinib: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Acemetacin: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Avoid combination

Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the antiplatelet effect of other Agents with Antiplatelet Properties. Monitor therapy

Alcohol (Ethyl): May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Specifically, the risk of GI bleeding may be increased with this combination. Monitor therapy

Aliskiren: Nonsteroidal Anti-Inflammatory Agents may diminish the antihypertensive effect of Aliskiren. Nonsteroidal Anti-Inflammatory Agents may enhance the nephrotoxic effect of Aliskiren. Management: Monitor renal function periodically in patients receiving aliskiren and any nonsteroidal anti-inflammatory agent. Patients at elevated risk of renal dysfunction include those who are elderly, are volume depleted, or have pre-existing renal dysfunction. Monitor therapy

Aminoglycosides: Nonsteroidal Anti-Inflammatory Agents may decrease the excretion of Aminoglycosides. Data only in premature infants. Monitor therapy

Aminolevulinic Acid (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Systemic). Avoid combination

Aminolevulinic Acid (Topical): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Topical). Monitor therapy

Angiotensin II Receptor Blockers: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Specifically, the combination may result in a significant decrease in renal function. Nonsteroidal Anti-Inflammatory Agents may diminish the therapeutic effect of Angiotensin II Receptor Blockers. The combination of these two agents may also significantly decrease glomerular filtration and renal function. Monitor therapy

Angiotensin-Converting Enzyme Inhibitors: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Specifically, the combination may result in a significant decrease in renal function. Nonsteroidal Anti-Inflammatory Agents may diminish the antihypertensive effect of Angiotensin-Converting Enzyme Inhibitors. Monitor therapy

Anticoagulants: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants. Exceptions: Bemiparin; Enoxaparin; Heparin. Monitor therapy

Apixaban: Naproxen may enhance the adverse/toxic effect of Apixaban. Specifically, the risk for bleeding may be increased. Naproxen may increase the serum concentration of Apixaban. Consider therapy modification

Bemiparin: Nonsteroidal Anti-Inflammatory Agents may enhance the anticoagulant effect of Bemiparin. Management: Avoid concomitant use of bemiparin and nonsteroidal anti-inflammatory agents (NSAIDs) due to the increased risk of bleeding. If concomitant use is unavoidable, monitor closely for signs and symptoms of bleeding. Consider therapy modification

Bemiparin: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Bemiparin. Management: Avoid concomitant use of bemiparin with antiplatelet agents. If concomitant use is unavoidable, monitor closely for signs and symptoms of bleeding. Consider therapy modification

Beta-Blockers: Nonsteroidal Anti-Inflammatory Agents may diminish the antihypertensive effect of Beta-Blockers. Exceptions: Levobunolol; Metipranolol. Monitor therapy

Bile Acid Sequestrants: May decrease the absorption of Nonsteroidal Anti-Inflammatory Agents. Consider therapy modification

Bisphosphonate Derivatives: Nonsteroidal Anti-Inflammatory Agents may enhance the adverse/toxic effect of Bisphosphonate Derivatives. Both an increased risk of gastrointestinal ulceration and an increased risk of nephrotoxicity are of concern. Monitor therapy

Cephalothin: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Cephalothin. Specifically, the risk for bleeding may be increased. Monitor therapy

Collagenase (Systemic): Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Collagenase (Systemic). Specifically, the risk of injection site bruising and/or bleeding may be increased. Monitor therapy

Corticosteroids (Systemic): May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents (Nonselective). Monitor therapy

CycloSPORINE (Systemic): Nonsteroidal Anti-Inflammatory Agents may enhance the nephrotoxic effect of CycloSPORINE (Systemic). Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of CycloSPORINE (Systemic). CycloSPORINE (Systemic) may increase the serum concentration of Nonsteroidal Anti-Inflammatory Agents. Management: Consider alternatives to nonsteroidal anti-inflammatory agents (NSAIDs). Monitor for evidence of nephrotoxicity, as well as increased serum cyclosporine concentrations and systemic effects (eg, hypertension) during concomitant therapy with NSAIDs. Consider therapy modification

Dabigatran Etexilate: Nonsteroidal Anti-Inflammatory Agents (Nonselective) may enhance the adverse/toxic effect of Dabigatran Etexilate. Specifically, the risk of bleeding may be increased. Management: A comprehensive risk to benefit assessment should be done for all patients before any concurrent use of dabigatran and nonsteroidal anti-inflammatory drugs (NSAIDs). If combined, monitor patients extra closely for signs and symptoms of bleeding. Consider therapy modification

Dasatinib: May enhance the anticoagulant effect of Agents with Antiplatelet Properties. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Monitor therapy

Deferasirox: Nonsteroidal Anti-Inflammatory Agents may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased. Monitor therapy

Deoxycholic Acid: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Deoxycholic Acid. Specifically, the risk for bleeding or bruising in the treatment area may be increased. Monitor therapy

Desmopressin: Nonsteroidal Anti-Inflammatory Agents may enhance the adverse/toxic effect of Desmopressin. Monitor therapy

Dexibuprofen: Nonsteroidal Anti-Inflammatory Agents may enhance the adverse/toxic effect of Dexibuprofen. Avoid combination

Dexketoprofen: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Avoid combination

Diclofenac (Systemic): May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Management: Seek alternatives to the combined use of diclofenac with other nonsteroidal anti-inflammatory agents (NSAIDs). Avoid the use of diclofenac/misoprostol with other NSAIDs. Consider therapy modification

Digoxin: Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of Digoxin. Monitor therapy

Drospirenone: Nonsteroidal Anti-Inflammatory Agents may enhance the hyperkalemic effect of Drospirenone. Monitor therapy

Edoxaban: Nonsteroidal Anti-Inflammatory Agents (Nonselective) may enhance the adverse/toxic effect of Edoxaban. Specifically, the risk of bleeding may be increased. Management: A comprehensive risk to benefit assessment should be done for all patients before any concurrent use of edoxaban and nonsteroidal anti-inflammatory drugs (NSAIDs). If combined, monitor patients extra closely for signs and symptoms of bleeding. Consider therapy modification

Enoxaparin: Nonsteroidal Anti-Inflammatory Agents may enhance the anticoagulant effect of Enoxaparin. Management: Discontinue nonsteroidal anti-inflammatory agents (NSAIDs) prior to initiating enoxaparin whenever possible. If concomitant administration is unavoidable, monitor closely for signs and symptoms of bleeding. Consider therapy modification

Enoxaparin: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Enoxaparin. Management: Discontinue antiplatelet agents prior to initiating enoxaparin whenever possible. If concomitant administration is unavoidable, monitor closely for signs and symptoms of bleeding. Consider therapy modification

Eplerenone: Nonsteroidal Anti-Inflammatory Agents may diminish the antihypertensive effect of Eplerenone. Nonsteroidal Anti-Inflammatory Agents may enhance the hyperkalemic effect of Eplerenone. Monitor therapy

Fat Emulsion (Fish Oil Based): May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Monitor therapy

Felbinac: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Monitor therapy

Floctafenine: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Avoid combination

Glucosamine: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Haloperidol: Nonsteroidal Anti-Inflammatory Agents may enhance the adverse/toxic effect of Haloperidol. Specifically including drowsiness and confusion. Monitor therapy

Heparin: Nonsteroidal Anti-Inflammatory Agents may enhance the anticoagulant effect of Heparin. Management: Decrease the dose of heparin or nonsteroidal anti-inflammatory agents (NSAIDs) if coadministration is required. Consider therapy modification

Heparin: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Heparin. Management: Decrease the dose of heparin or agents with antiplatelet properties if coadministration is required. Consider therapy modification

Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Bleeding may occur. Management: Avoid combination when possible. If used, monitor more closely for evidence of bleeding. Discontinue herbal products with anticoagulant or antiplatelet actions 2 weeks prior to surgical, dental, or invasive procedures. Consider therapy modification

Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Bleeding may occur. Management: Concomitant treatment with these agents should generally be avoided. If used concomitantly, increased diligence in monitoring for adverse effects (eg, bleeding, bruising, altered mental status due to CNS bleeds) must be employed. Consider therapy modification

HydrALAZINE: Nonsteroidal Anti-Inflammatory Agents may diminish the antihypertensive effect of HydrALAZINE. Monitor therapy

Ibritumomab Tiuxetan: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Ibritumomab Tiuxetan. Both agents may contribute to impaired platelet function and an increased risk of bleeding. Monitor therapy

Ibrutinib: May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Monitor therapy

Inotersen: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Ketorolac (Nasal): May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Avoid combination

Ketorolac (Systemic): May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Avoid combination

Limaprost: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Lithium: Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of Lithium. Consider therapy modification

Loop Diuretics: Nonsteroidal Anti-Inflammatory Agents may diminish the diuretic effect of Loop Diuretics. Loop Diuretics may enhance the nephrotoxic effect of Nonsteroidal Anti-Inflammatory Agents. Management: Monitor for evidence of kidney injury or decreased therapeutic effects of loop diuretics with concurrent use of an NSAID. Consider avoiding concurrent use in CHF or cirrhosis. Concomitant use of bumetanide with indomethacin is not recommended. Consider therapy modification

Macimorelin: Nonsteroidal Anti-Inflammatory Agents may diminish the diagnostic effect of Macimorelin. Avoid combination

MetFORMIN: Nonsteroidal Anti-Inflammatory Agents may enhance the adverse/toxic effect of MetFORMIN. Monitor therapy

Methotrexate: Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of Methotrexate. Management: Alternative anti-inflammatory therapy should be considered whenever possible, especially if the patient is receiving higher, antineoplastic doses of methotrexate. Consider therapy modification

Mifamurtide: Nonsteroidal Anti-Inflammatory Agents may diminish the therapeutic effect of Mifamurtide. Avoid combination

Morniflumate: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Avoid combination

Multivitamins/Fluoride (with ADE): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Multivitamins/Minerals (with ADEK, Folate, Iron): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Multivitamins/Minerals (with AE, No Iron): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Naftazone: May enhance the antiplatelet effect of Nonsteroidal Anti-Inflammatory Agents. Monitor therapy

Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective): Nonsteroidal Anti-Inflammatory Agents may enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective). Avoid combination

Obinutuzumab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased. Monitor therapy

Omacetaxine: Nonsteroidal Anti-Inflammatory Agents may enhance the adverse/toxic effect of Omacetaxine. Specifically, the risk for bleeding-related events may be increased. Management: Avoid concurrent use of nonsteroidal antiinflammatory drugs (NSAIDs) with omacetaxine in patients with a platelet count of less than 50,000/uL. Avoid combination

Omega-3 Fatty Acids: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Pelubiprofen: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Avoid combination

Pentosan Polysulfate Sodium: May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Specifically, the risk of bleeding may be increased by concurrent use of these agents. Monitor therapy

Pentoxifylline: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Phenylbutazone: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Avoid combination

Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. Monitor therapy

Potassium-Sparing Diuretics: Nonsteroidal Anti-Inflammatory Agents may diminish the antihypertensive effect of Potassium-Sparing Diuretics. Nonsteroidal Anti-Inflammatory Agents may enhance the hyperkalemic effect of Potassium-Sparing Diuretics. Monitor therapy

PRALAtrexate: Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of PRALAtrexate. More specifically, NSAIDS may decrease the renal excretion of pralatrexate. Management: Closely monitor for increased pralatrexate serum levels and/or toxicity if used concomitantly with an NSAID. Monitor for decreased pralatrexate serum levels with NSAID discontinuation. Monitor therapy

Probenecid: May increase the serum concentration of Nonsteroidal Anti-Inflammatory Agents. Monitor therapy

Prostacyclin Analogues: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Prostaglandins (Ophthalmic): Nonsteroidal Anti-Inflammatory Agents may diminish the therapeutic effect of Prostaglandins (Ophthalmic). Nonsteroidal Anti-Inflammatory Agents may also enhance the therapeutic effects of Prostaglandins (Ophthalmic). Monitor therapy

Quinolones: Nonsteroidal Anti-Inflammatory Agents may enhance the neuroexcitatory and/or seizure-potentiating effect of Quinolones. Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of Quinolones. Monitor therapy

Rivaroxaban: Nonsteroidal Anti-Inflammatory Agents (Nonselective) may enhance the adverse/toxic effect of Rivaroxaban. Specifically, the risk of bleeding may be increased. Management: A comprehensive risk to benefit assessment should be done for all patients before any concurrent use of rivaroxaban and nonsteroidal anti-inflammatory drugs (NSAIDs). If combined, monitor patients extra closely for signs and symptoms of bleeding. Consider therapy modification

Salicylates: Nonsteroidal Anti-Inflammatory Agents (Nonselective) may enhance the adverse/toxic effect of Salicylates. An increased risk of bleeding may be associated with use of this combination. Nonsteroidal Anti-Inflammatory Agents (Nonselective) may diminish the cardioprotective effect of Salicylates. Salicylates may decrease the serum concentration of Nonsteroidal Anti-Inflammatory Agents (Nonselective). Exceptions: Choline Magnesium Trisalicylate. Consider therapy modification

Salicylates: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Salicylates. Increased risk of bleeding may result. Monitor therapy

Selective Serotonin Reuptake Inhibitors: May enhance the antiplatelet effect of Nonsteroidal Anti-Inflammatory Agents (Nonselective). Nonsteroidal Anti-Inflammatory Agents (Nonselective) may diminish the therapeutic effect of Selective Serotonin Reuptake Inhibitors. Management: Consider alternatives to NSAIDs. Monitor for evidence of bleeding and diminished antidepressant effects. It is unclear whether COX-2-selective NSAIDs reduce risk. Consider therapy modification

Serotonin/Norepinephrine Reuptake Inhibitors: May enhance the antiplatelet effect of Nonsteroidal Anti-Inflammatory Agents (Nonselective). Monitor therapy

Sincalide: Drugs that Affect Gallbladder Function may diminish the therapeutic effect of Sincalide. Management: Consider discontinuing drugs that may affect gallbladder motility prior to the use of sincalide to stimulate gallbladder contraction. Consider therapy modification

Sodium Phosphates: May enhance the nephrotoxic effect of Nonsteroidal Anti-Inflammatory Agents. Specifically, the risk of acute phosphate nephropathy may be enhanced. Management: Consider avoiding this combination by temporarily suspending treatment with NSAIDs, or seeking alternatives to oral sodium phosphate bowel preparation. If the combination cannot be avoided, maintain adequate hydration and monitor renal function closely. Consider therapy modification

Tacrolimus (Systemic): Nonsteroidal Anti-Inflammatory Agents may enhance the nephrotoxic effect of Tacrolimus (Systemic). Monitor therapy

Talniflumate: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Avoid combination

Tenofovir Products: Nonsteroidal Anti-Inflammatory Agents may enhance the nephrotoxic effect of Tenofovir Products. Management: Seek alternatives to these combinations whenever possible. Avoid use of tenofovir with multiple NSAIDs or any NSAID given at a high dose. Consider therapy modification

Tenoxicam: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Avoid combination

Thiazide and Thiazide-Like Diuretics: May enhance the nephrotoxic effect of Nonsteroidal Anti-Inflammatory Agents. Nonsteroidal Anti-Inflammatory Agents may diminish the therapeutic effect of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Thrombolytic Agents: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Thrombolytic Agents. Monitor therapy

Tipranavir: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Tolperisone: Nonsteroidal Anti-Inflammatory Agents may enhance the adverse/toxic effect of Tolperisone. Specifically, the risk of hypersensitivity reactions may be increased. Tolperisone may enhance the therapeutic effect of Nonsteroidal Anti-Inflammatory Agents. Monitor therapy

Tricyclic Antidepressants (Tertiary Amine): May enhance the antiplatelet effect of Nonsteroidal Anti-Inflammatory Agents (Nonselective). Monitor therapy

Urokinase: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Urokinase. Avoid combination

Vancomycin: Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of Vancomycin. Monitor therapy

Verteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin. Monitor therapy

Vitamin E (Systemic): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Vitamin K Antagonists (eg, warfarin): Nonsteroidal Anti-Inflammatory Agents (Nonselective) may enhance the anticoagulant effect of Vitamin K Antagonists. Management: Consider alternatives to this combination when possible. If the combination must be used, monitor coagulation status closely and advise patients to promptly report any evidence of bleeding or bruising. Consider therapy modification

Zaltoprofen: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Avoid combination

Zanubrutinib: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Test Interactions

Naproxen may interfere with 5-HIAA urinary assays; due to an interaction with m-dinitrobenzene, naproxen should be discontinued 72 hours before adrenal function testing if the Porter-Silber test is used. May lead to false-positive aldosterone/renin ratio (ARR) (Funder 2016).

Adverse Reactions

1% to 10%:

Cardiovascular: Edema (3% to 9%), palpitations (<3%)

Central nervous system: Dizziness (≤9%), drowsiness (3% to 9%), headache (3% to 9%), vertigo (<3%)

Dermatologic: Pruritus (3% to 9%), skin rash (3% to 9%), ecchymoses (3% to 9%), diaphoresis (<3%)

Endocrine & metabolic: Fluid retention (3% to 9%), increased thirst (<3%)

Gastrointestinal: Abdominal pain (3% to 9%), constipation (3% to 9%), nausea (3% to 9%), heartburn (3% to 9%), diarrhea (<3%), dyspepsia (<3%), stomatitis (<3%), flatulence, gastrointestinal hemorrhage, gastrointestinal perforation, gastrointestinal ulcer, vomiting

Hematologic & oncologic: Hemolysis (3% to 9%), purpura (<3%), anemia, prolonged bleeding time

Hepatic: Increased liver enzymes

Ophthalmic: Visual disturbance (<3%)

Otic: Tinnitus (3% to 9%), auditory disturbance (<3%)

Renal: Renal function abnormality

Respiratory: Dyspnea (3% to 9%)

<1%, postmarketing, and/or case reports: Abnormal dreams, agranulocytosis, alopecia, anaphylactoid reaction, anaphylaxis, angioedema, aphthous stomatitis, aseptic meningitis, asthma, blurred vision, cardiac arrhythmia, cardiac failure, cognitive dysfunction, colitis, coma, confusion, conjunctivitis, cystitis, depression, dysuria, eosinophilia, eosinophilic pneumonitis, erythema multiforme, exfoliative dermatitis, fever, glossitis, granulocytopenia, hallucination, hematemesis, hepatic failure, hepatitis, hepatotoxicity (idiosyncratic) (Chalasani, 2014), hyperglycemia, hypertension, hypoglycemia, hypotension, infection, interstitial nephritis, melena, jaundice, leukopenia, lymphadenopathy, menstrual disease, malaise, myalgia, myasthenia, myocardial infarction, oliguria, pancreatitis, pancytopenia, paresthesia, pneumonia, polyuria, proteinuria, rectal hemorrhage, renal failure, renal papillary necrosis, respiratory depression, sepsis, skin photosensitivity, Stevens-Johnson syndrome, tachycardia, seizure, syncope, thrombocytopenia, toxic epidermal necrolysis, vasculitis

Warnings/Precautions

Concerns related to adverse effects:

• Anaphylactoid reactions: Even in patients without prior exposure anaphylactoid reactions may occur; patients with "aspirin triad" (bronchial asthma, aspirin intolerance, rhinitis) may be at increased risk. Contraindicated in patients who experience bronchospasm, asthma, rhinitis, or urticaria with NSAID or aspirin therapy.
• Cardiovascular events: [US Boxed Warning]: NSAIDs cause an increased risk of serious (and potentially fatal) adverse cardiovascular thrombotic events, including MI and stroke. Risk may occur early during treatment and may increase with duration of use. Relative risk appears to be similar in those with and without known cardiovascular disease or risk factors for cardiovascular disease; however, absolute incidence of serious cardiovascular thrombotic events (which may occur early during treatment) was higher in patients with known cardiovascular disease or risk factors and in those receiving higher doses. New-onset hypertension or exacerbation of hypertension may occur (NSAIDs may also impair response to ACE inhibitors, thiazide diuretics, or loop diuretics); may contribute to cardiovascular events; monitor blood pressure; use with caution in patients with hypertension. May cause sodium and fluid retention, use with caution in patients with edema. Avoid use in heart failure (ACCF/AHA [Yancy 2013]). Avoid use in patients with a recent MI unless benefits outweigh risk of cardiovascular thrombotic events. Use the lowest effective dose for the shortest duration of time, consistent with individual patient goals, to reduce risk of cardiovascular events; alternate therapies should be considered for patients at high risk.
• CNS effects: May cause drowsiness, dizziness, blurred vision, and other neurologic effects which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving). Discontinue use with blurred or diminished vision and perform ophthalmologic exam. Periodically evaluate vision in all patients receiving long term therapy.
• Gastrointestinal events: [US Boxed Warning]: NSAIDs cause increased risk of serious gastrointestinal inflammation, ulceration, bleeding, and perforation (may be fatal); elderly patients and patients with history of peptic ulcer disease and/or GI bleeding are at greater risk of serious GI events. These events may occur at any time during therapy and without warning. Avoid use in patients with active GI bleeding. Use caution with a history of GI ulcers, concurrent therapy known to increase the risk of GI bleeding (eg, aspirin, anticoagulants and/or corticosteroids, selective serotonin reuptake inhibitors), advanced hepatic disease, coagulopathy, smoking, use of alcohol, or in elderly or debilitated patients. Use the lowest effective dose for the shortest duration of time, consistent with individual patient goals, to reduce risk of GI adverse events; alternate therapies should be considered for patients at high risk. When used concomitantly with aspirin, a substantial increase in the risk of gastrointestinal complications (eg, ulcer) occurs; concomitant gastroprotective therapy (eg, proton pump inhibitors) is recommended (Bhatt 2008).
• Hematologic effects: Platelet adhesion and aggregation may be decreased; may prolong bleeding time; patients with coagulation disorders or who are receiving anticoagulants should be monitored closely. Anemia may occur; patients on long-term NSAID therapy should be monitored for anemia. Rarely, NSAID use has been associated with potentially severe blood dyscrasias (eg, agranulocytosis, thrombocytopenia, aplastic anemia).
• Hepatic effects: Transaminase elevations have been reported with use; closely monitor patients with any abnormal LFT. Rare (sometimes fatal) severe hepatic reactions (eg, fulminant hepatitis, hepatic necrosis, hepatic failure) have occurred with NSAID use; discontinue immediately if signs or symptoms of hepatic disease develop or if systemic manifestations occur.
• Hyperkalemia: NSAID use may increase the risk of hyperkalemia, particularly in the elderly, diabetics, renal disease, and with concomitant use of other agents capable of inducing hyperkalemia (eg, ACE-inhibitors). Monitor potassium closely.
• Renal effects: NSAID use may compromise existing renal function; dose-dependent decreases in prostaglandin synthesis may result from NSAID use, reducing renal blood flow which may cause renal decompensation (usually reversible). Patients with impaired renal function, dehydration, hypovolemia, heart failure, hepatic impairment, those taking diuretics, and ACE inhibitors, and the elderly are at greater risk of renal toxicity. Rehydrate patient before starting therapy; monitor renal function closely. Long-term NSAID use may result in renal papillary necrosis and other renal injury.
• Skin reactions: NSAIDs may cause potentially fatal serious skin adverse events including exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN); may occur without warning; discontinue use at first sign of skin rash (or any other hypersensitivity).

Disease-related concerns:

• Aseptic meningitis: May increase the risk of aseptic meningitis, especially in patients with systemic lupus erythematosus (SLE) and mixed connective tissue disorders.
• Asthma: Contraindicated in patients with aspirin-sensitive asthma; severe and potentially fatal bronchospasm may occur. Use caution in patients with other forms of asthma.
• Bariatric surgery: Gastric ulceration: Avoid chronic use of oral nonselective NSAIDs after bariatric surgery; development of anastomotic ulcerations/perforations may occur (Bhangu 2014; Mechanick 2013). Short-term use of celecoxib or IV ketorolac are recommended as part of a multimodal pain management strategy for postoperative pain (Chou 2016; Horsley 2019; Thorell 2016).
• Coronary artery bypass graft surgery: [US Boxed Warning]: Use is contraindicated in the setting of coronary artery bypass graft (CABG) surgery. Risk of MI and stroke may be increased with use following CABG surgery.
• Hepatic impairment: Use with caution in patients with hepatic impairment; patients with advanced hepatic disease are at an increased risk of GI bleeding with NSAIDs.
• Renal impairment: Avoid use in patients with advanced renal disease; discontinue use with persistent or worsening abnormal renal function tests.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Elderly patients are at greater risk for serious GI, cardiovascular, and/or renal adverse events; use with caution.
• Pediatric: Not for self-medication (OTC use) in children <12 years.

Other warnings/precautions:

• Self-medication (OTC use): Prior to self-medication, patients should contact healthcare provider if they have had recurring stomach pain or upset, ulcers, bleeding problems, asthma, high blood pressure, heart or kidney disease, other serious medical problems, are currently taking a diuretic, anticoagulant, other NSAIDs, or are ≥60 years of age. Recommended dosages and duration should not be exceeded, due to an increased risk of GI bleeding, MI, and stroke. Patients should stop use and consult a healthcare provider if symptoms get worse, newly appear, or continue; if an allergic reaction occurs; if feeling faint, vomit blood or have bloody/black stools; if having difficulty swallowing or heartburn, or if fever lasts for >3 days or pain >10 days. Consuming ≥3 alcoholic beverages/day or taking longer than recommended may increase the risk of GI bleeding.
• Surgical/dental procedures: Withhold for at least 4 to 6 half-lives prior to surgical or dental procedures.

Monitoring Parameters

CBC (if hemoglobin ≤10 g at initiation, continue to monitor hemoglobin periodically during long-term therapy), chemistry profile (periodically during long-term therapy), liver function tests, renal function tests (urine output, serum BUN and creatinine), blood pressure (at initiation and during therapy), signs/symptoms of fluid retention, periodic ophthalmic exam (with any vision changes occurring during long-term therapy), signs of bleeding (occult or gross blood loss).

Pregnancy

Pregnancy Considerations

Naproxen crosses the placenta (Brogden 1975). Birth defects have been observed following in utero NSAID exposure in some studies; however, data is conflicting (Bloor 2013). Nonteratogenic effects, including prenatal constriction of the ductus arteriosus, persistent pulmonary hypertension of the newborn, oligohydramnios, necrotizing enterocolitis, renal dysfunction or failure, and intracranial hemorrhage have been observed in the fetus/neonate following in utero NSAID exposure. In addition, nonclosure of the ductus arteriosus postnatally may occur and be resistant to medical management (Bermas 2014; Bloor 2013). Because NSAIDs may cause premature closure of the ductus arteriosus, product labeling for naproxen specifically states use should be avoided starting at 30-weeks gestation. Use of NSAIDs can be considered for the treatment of mild rheumatoid arthritis flares in pregnant women; however, use should be minimized or avoided early and late in pregnancy (Bermas 2014; Saavedra Salinas 2015).

The chronic use of NSAIDs in women of reproductive age may be associated with infertility that is reversible upon discontinuation of the medication. Consider discontinuing use in women having difficulty conceiving or those undergoing investigation of fertility. The use of NSAIDs close to conception may be associated with an increased risk of miscarriage (Bloor 2013; Bermas 2014).

Patient Education

What is this drug used for?

• It is used to ease pain, swelling, and fever.
• It is used to ease painful period (menstrual) cycles.
• It is used to treat arthritis.
• It is used to treat ankylosing spondylitis.
• It is used to treat gout attacks.
• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Heartburn
• Abdominal pain
• Nausea
• Constipation
• Fatigue

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Abdominal ulcers like severe abdominal or back pain; black, tarry, or bloody stools; vomiting blood or vomit that looks like coffee grounds; or weight gain or abnormal swelling
• Kidney problems like not able to pass urine, blood in the urine, change in amount of urine passed, or weight gain
• Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding
• Cerebrovascular disease like change in strength on one side is greater than the other, trouble speaking or thinking, change in balance, or vision changes
• High potassium like abnormal heartbeat, confusion, dizziness, passing out, weak, shortness of breath, numbness or tingling feeling
• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin
• Shortness of breath
• Excessive weight gain
• Swelling of arms or legs
• Chest pain
• Fast heartbeat
• Severe headache
• Severe dizziness
• Passing out
• Vision changes
• Severe loss of strength and energy
• Noise or ringing in the ears
• Severe abdominal pain
• Severe back pain
• Stevens-Johnson syndrome/toxic epidermal necrolysis like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in mouth, throat, nose, or eyes.
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.