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Naproxen

Pronunciation

Pronunciation

(na PROKS en)

Index Terms

  • Naproxen Sodium

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)]

Cream, External:

EnovaRX-Naproxen: 10% (60 g, 120 g) [contains cetyl alcohol]

Equipto-Naproxen: 10% (120 g)

Naproderm: 15% (60 g [DSC])

Kit, Combination:

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

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

Suspension, Oral:

Naprosyn: 125 mg/5 mL (480 mL)

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

Generic: 125 mg/5 mL (500 mL)

Tablet, Oral:

Naprosyn: 250 mg [DSC] [scored]

Naprosyn: 375 mg [DSC]

Naprosyn: 500 mg [scored]

Naproxen Kit: 500 mg [scored]

Generic: 250 mg, 375 mg, 500 mg

Tablet, Oral, as sodium:

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

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

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

All Day Relief: 220 mg

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

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

Anaprox: 275 mg [DSC]

Anaprox DS: 550 mg [scored]

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

Mediproxen: 220 mg

Generic: 220 mg, 275 mg, 550 mg

Tablet Delayed Release, Oral:

EC-Naprosyn: 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, 500 mg (14s) and 750 mg (6s) [DSC]

Generic: 375 mg, 500 mg

Brand Names: U.S.

  • Aleve [OTC]
  • All Day Pain Relief [OTC]
  • All Day Relief [OTC]
  • Anaprox DS
  • Anaprox [DSC]
  • EC-Naprosyn
  • EnovaRX-Naproxen
  • Equipto-Naproxen
  • Flanax Pain Relief
  • Flanax Pain Relief [OTC]
  • Mediproxen [OTC]
  • Naprelan
  • Naproderm [DSC]
  • Naprosyn
  • Naproxen Comfort Pac
  • Naproxen DR
  • Naproxen Kit

Pharmacologic Category

  • Analgesic, Nonopioid
  • Nonsteroidal Anti-inflammatory Drug (NSAID), Oral

Pharmacology

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.

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

Special Populations: Renal Function Impairment

Metabolites and conjugates may accumulate.

Use: Labeled Indications

Acute gout/Ankylosing spondylitis/Bursitis/Juvenile arthritis/Juvenile rheumatoid arthritis/Osteoarthritis/Rheumatoid arthritis/Tendonitis (Rx products only): Relief of the signs and symptoms of acute gout, ankylosing spondylitis, bursitis, juvenile arthritis (excluding ER tablets), juvenile rheumatoid arthritis (oral suspension only), 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: Unlabeled

Migraine prophylaxis

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 U.S. labeling): Active 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).

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: Oral: Initial: 750 mg, followed by 250 mg every 8 hours until attack subsides

Naproxen extended-release tablets: Initial: 1,000 to 1,500 mg once daily followed by 1,000 mg once daily until attack subsides

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.

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.

Juvenile idiopathic arthritis: Children >2 years and Adolescents: Oral: Note: Oral suspension is recommended: 10 mg/kg/day in 2 divided doses (up to 15 mg/kg/day has been tolerated). Do not exceed 15 mg/kg/day.

OTC labeling: Pain, fever: Children ≥12 years and Adolescents: Oral: Refer to adult dosing.

Ankylosing spondylitis, osteoarthritis, rheumatoid arthritis: Adolescents ≥16 years: Rectal suppository [Canadian product]: Refer to adult dosing.

Dosing: Renal Impairment

CrCl ≥30 mL/minute: There are no specific dosage adjustments provided in the manufacturer’s labeling; use with caution and consider using a reduced dose. Use is not recommended in patients with moderate renal impairment.

CrCl <30 mL/minute

US labeling: Use is not recommended; avoid use in patients with advanced renal disease.

Canadian labeling: Use is contraindicated.

KDIGO 2012 guidelines provide the following recommendations for NSAIDs:

eGFR 30 to <60 mL/minute/1.73 m2:Temporarily discontinue in patients with intercurrent disease that increases risk of acute kidney injury.

eGFR <30 mL/minute/1.73 m2: Avoid use.

Dosing: Hepatic Impairment

There are no specific dosage adjustments provided in the manufacturer’s labeling; use with caution and consider using a reduced dose. Canadian labeling contraindicates use in severe impairment or active liver disease.

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

Drug may cause GI upset, bleeding, ulceration, perforation; take with food or milk to minimize GI upset.

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

ACE 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 ACE Inhibitors. Monitor therapy

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: Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid. 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

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

Anticoagulants: Nonsteroidal Anti-Inflammatory Agents may enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Antidepressants (Tricyclic, Tertiary Amine): May enhance the antiplatelet effect of NSAID (Nonselective). 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

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 NSAID (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. Specifically, elevated diclofenac concentrations have been reported. Management: Consider alternatives to nonsteroidal anti-inflammatory agents (NSAIDs). Monitor for evidence of nephrotoxicity, as well as increased serum cyclosporine concentrations and systemic effects (e.g., hypertension) during concomitant therapy with NSAIDs. Consider therapy modification

Dabigatran Etexilate: NSAID (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. 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

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: NSAID (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

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

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

Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Bleeding may occur. 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: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Ibritumomab. 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

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

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

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

NSAID (COX-2 Inhibitor): Nonsteroidal Anti-Inflammatory Agents may enhance the adverse/toxic effect of NSAID (COX-2 Inhibitor). 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

PEMEtrexed: NSAID (Nonselective) may increase the serum concentration of PEMEtrexed. Management: Patients with mild-to-moderate renal insufficiency (estimated creatinine clearance 45-79 mL/min) should avoid NSAIDs for 2-5 days prior to, the day of, and 2 days after pemetrexed. Consider therapy modification

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

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

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

Rivaroxaban: NSAID (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: NSAID (Nonselective) may enhance the adverse/toxic effect of Salicylates. An increased risk of bleeding may be associated with use of this combination. NSAID (Nonselective) may diminish the cardioprotective effect of Salicylates. Salicylates may decrease the serum concentration of NSAID (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 NSAID (Nonselective). NSAID (Nonselective) may diminish the therapeutic effect of Selective Serotonin Reuptake Inhibitors. Management: Consider using alternative analgesics, when appropriate, and/or addition of a gastroprotective agent. Monitor patients closely for signs/symptoms of bleeding, and for evidence of diminished SSRI effectiveness with concurrent use. Consider therapy modification

Serotonin/Norepinephrine Reuptake Inhibitors: May enhance the antiplatelet effect of NSAID (Nonselective). Monitor therapy

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

Tositumomab and Iodine I 131 Tositumomab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Tositumomab and Iodine I 131 Tositumomab. Specifically, the risk of bleeding-related adverse events may be increased. Monitor therapy

Treprostinil: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Bleeding may occur. 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: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

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

Vitamin K Antagonists (eg, warfarin): NSAID (Nonselective) may enhance the anticoagulant effect of Vitamin K Antagonists. Consider therapy modification

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 interfere with urine detection of cannabinoids and barbiturates (false-positives).

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% (Limited to important or life-threatening): 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

ALERT: U.S. Boxed Warning

Serious cardiovascular thrombotic events:

Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction (MI), and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use.

Naproxen is contraindicated in the setting of coronary artery bypass graft (CABG) surgery.

Serious gastrointestinal bleeding, ulceration, and perforation:

NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events, including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events

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. Canadian labeling contraindicates use with active peptic ulcers, GI bleeding, or inflammatory bowel disease. 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). Canadian labeling contraindicates use in patients with known hyperkalemia. 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.

• 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. Canadian labeling contraindicates use in severe impairment or with active liver disease.

• Renal impairment: Avoid use in patients with advanced renal disease; discontinue use with persistent or worsening abnormal renal function tests. Canadian labeling contraindicates use in severe renal impairment (CrCl <30 mL/minute) or deteriorating renal disease.

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. Canadian labeling contraindicates use of certain dosage forms based on age (refer to Contraindications for specific recommendations).

Dosage forms specific issues:

• Naproxen sodium: Naproxen sodium contains about 1 mEq of sodium per 250 mg of naproxen; consider this in patients whose overall intake of sodium must be severely restricted.

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, chemistry profile occult blood loss, and periodic liver function test renal function (urine output, serum BUN and creatinine); blood pressure; periodic ophthalmic exam with long-term therapy.

Pregnancy Considerations

Adverse events have been observed in some animal reproduction studies. Naproxen crosses the placenta and can be detected in fetal tissue and the serum of newborn infants following in utero exposure. NSAID exposure during the first trimester is not strongly associated with congenital malformations; however, cardiovascular anomalies and cleft palate have been observed following NSAID exposure in some studies. The use of a NSAID close to conception may be associated with an increased risk of miscarriage. Nonteratogenic effects have been observed following NSAID administration during the third trimester including: Myocardial degenerative changes, prenatal constriction of the ductus arteriosus, fetal tricuspid regurgitation, failure of the ductus arteriosus to close postnatally; renal dysfunction or failure, oligohydramnios; gastrointestinal bleeding or perforation, increased risk of necrotizing enterocolitis; intracranial bleeding (including intraventricular hemorrhage), platelet dysfunction with resultant bleeding; pulmonary hypertension. Because they may cause premature closure of the ductus arteriosus, use of NSAIDs late in pregnancy should be avoided (use after 31 or 32 weeks gestation is not recommended by some clinicians). The Canadian labeling contraindicates use during the third trimester of pregnancy. The chronic use of NSAIDs in women of reproductive age may be associated with infertility that is reversible upon discontinuation of the medication. A registry is available for pregnant women exposed to autoimmune medications including naproxen. For additional information contact the Organization of Teratology Information Specialists, OTIS Autoimmune Diseases Study, at (877) 311-8972.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience pyrosis, diarrhea, constipation, flatulence, or fatigue. Have patient report immediately to prescriber signs of hepatic impairment, dyspnea, excessive weight gain, edema of extremities, angina, tachycardia, strength differences from one side to another, difficulty speaking or thinking, change in balance, blurred vision, significant headache, severe dizziness, syncope, considerable asthenia, tinnitus, mood changes, depression, intolerable nausea, severe dyspepsia, considerable back pain, melena, hematemesis, ecchymosis, hemorrhaging, urinary retention, oliguria, or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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