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Naproxen: Drug information

Naproxen: Drug information
(For additional information see "Naproxen: Patient drug information" and see "Naproxen: Pediatric drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
ALERT: US 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

Brand Names: US
  • Aleve [OTC];
  • All Day Pain Relief [OTC] [DSC];
  • All Day Relief [OTC];
  • Anaprox DS;
  • EC-Naprosyn;
  • EC-Naproxen;
  • Flanax Pain Relief [OTC] [DSC];
  • GoodSense Naproxen Sodium [OTC];
  • Mediproxen [OTC];
  • Naprelan;
  • Naprosyn;
  • Naproxen Comfort Pac [DSC]
Brand Names: Canada
  • Anaprox;
  • Anaprox DS;
  • APO-Napro-Na;
  • APO-Naproxen;
  • APO-Naproxen EC;
  • Naprosyn;
  • Naproxen-250;
  • Naproxen-500;
  • Naproxen-Na;
  • Naxen EC;
  • Pediapharm Naproxen;
  • PMS-Naproxen EC;
  • PMS-Naproxen [DSC];
  • PRO-Naproxen EC;
  • TEVA-Naproxen;
  • TEVA-Naproxen EC;
  • TEVA-Naproxen Sodium;
  • TEVA-Naproxen Sodium DS
Pharmacologic Category
  • Analgesic, Nonopioid;
  • Nonsteroidal Anti-inflammatory Drug (NSAID), Oral
Dosing: Adult

Note: Dosing units: Naproxen is available as naproxen base and sodium salt. All doses in this monograph are expressed as base; 200 mg naproxen base is equivalent to 220 mg naproxen sodium. Formulations: For relief of acute pain, naproxen sodium formulations may be preferred due to more rapid onset. Safety: Use the lowest effective dose for the shortest duration of time. Avoid or use with caution in patients at risk for or with existing cardiovascular disease, GI disease, kidney impairment, chronic liver disease, or a bleeding diathesis due to greater risk for adverse events. Consider administering in combination with a proton pump inhibitor in patients at risk for GI bleeding (eg, taking dual antiplatelet therapy or an anticoagulant, ≥60 years of age, high doses) (ACCF/ACG/AHA [Abraham 2010]; ACCF/ACG/AHA [Bhatt 2008a]).

Abnormal uterine bleeding, nonacute

Abnormal uterine bleeding, nonacute (alternative agent) (off-label use): Note: Not indicated for management of acute abnormal bleeding (ie, excessively heavy or prolonged bleeding that requires urgent evaluation). Alternative agent for patients who cannot or choose not to use hormonal therapies (Kaunitz 2022).

Oral: Immediate release: 500 mg at the first sign of menses; may repeat 500 mg 3 to 5 hours later, followed by 250 to 500 mg twice daily for 2 to 3 days or until cessation of bleeding; maximum dose: 1 g/day (Bofill Rodriguez 2019; Fraser 1991; Kaunitz 2022; Lethaby 2019; Rybo 1981; Ylikorkala 1986).

Anti-inflammatory

Anti-inflammatory (eg, for arthritis associated with rheumatic disease):

Oral:

Immediate release: 250 to 500 mg every 12 hours; maximum dose: 1.5 g/day.

Extended release: 750 mg to 1 g once daily; maximum dose: 1.5 g/day.

Note: Some experts generally recommend a maximum dose of 1 g/day for chronic use, except during a disease flare when 1.25 to 1.5 g/day may be considered for several weeks until flare resolves (Solomon 2022).

Dysmenorrhea, primary

Dysmenorrhea, primary:

Oral:

Immediate release: Initial: 500 mg once, begin at menses onset or 1 to 2 days prior to onset of menses for severe symptoms; then 500 mg every 12 hours as needed or 250 mg every 6 to 8 hours as needed; maximum dose: 1.25 g/day on day 1, then 1 g/day thereafter; usual duration: 1 to 5 days (Bofill Rodriguez 2019; Smith 2020; manufacturer’s labeling).

Extended release: Initial: 1 g once daily as needed; begin at menses onset or 1 to 2 days prior to onset of menses for severe symptoms; may increase to a maximum of 1.5 g once daily if needed; usual duration: 1 to 5 days (Bofill Rodriguez 2019; Smith 2020; manufacturer’s labeling).

Fever

Fever (alternative agent):

Oral: OTC labeling (patient-guided therapy): Immediate release: Initial: 200 to 400 mg once, followed by 200 mg every 8 to 12 hours as needed; maximum dose: 400 mg in any 8- to 12-hour period or 600 mg in a 24-hour period.

Gout, prophylaxis during initiation of urate-lowering therapy

Gout, prophylaxis during initiation of urate-lowering therapy (alternative agent):

Note: For use in patients not able to tolerate or with contraindications to colchicine (ACR [FitzGerald 2020]; EULAR [Richette 2017]; Perez-Ruiz 2020).

Oral: Immediate release: 250 mg twice daily (ACR [FitzGerald 2020]; EULAR [Richette 2017]; Perez-Ruiz 2020).

Duration of prophylaxis:

Patients without tophi: ≥3 to 6 months after initiating urate-lowering therapy (ACR [FitzGerald 2020]; EULAR [Richette 2017]; Perez-Ruiz 2020).

Patients with ≥1 tophi: Optimal duration is uncertain; some experts continue prophylaxis ≥6 months; some patients with severe disease may require >12 months prophylaxis (Perez-Ruiz 2020).

Gout, treatment

Gout, treatment (acute flares):

Note: Some experts reserve use for patients who are not candidates for intra-articular glucocorticoids or when intra-articular glucocorticoid administration is not feasible (Gaffo 2022).

Oral:

Immediate release: Initial: 500 mg twice daily within 24 to 48 hours of flare onset; reduce dose as symptoms improve; discontinue 2 to 3 days after resolution of clinical signs. Usual duration: 5 to 7 days (ACR [FitzGerald 2020]; Gaffo 2022; Janssens 2008; Roddy 2020).

Extended release: Initial: 1 to 1.5 g once, followed by 1 g once daily; initiate within 24 to 48 hours of flare onset; reduce dose as symptoms improve; discontinue 2 to 3 days after resolution of clinical signs. Usual duration: 5 to 7 days (ACR [FitzGerald 2020]; Gaffo 2022; manufacturer’s labeling).

Migraine, acute treatment

Migraine, acute treatment (off-label use):

Note: For use as monotherapy in mild to moderate attacks not associated with vomiting or severe nausea; may be used in combination with triptans for severe migraine (CHS [Worthington 2013]; Schwedt 2021).

Oral: Immediate release: 500 to 750 mg once (CHS [Worthington 2013]).

Pain

Pain (monotherapy or as adjunctive agent):

Oral:

Immediate release: Initial: 500 mg once, followed by 250 to 500 mg every 12 hours as needed or 250 mg every 6 to 8 hours as needed; maximum dose: 1.25 g on day 1, then 1 g/day thereafter. For postoperative pain, doses may be scheduled initially (Schwenk 2020, manufacturer’s labeling).

Extended release: 1 g once daily; may increase to 1.5 g once daily for acute pain, then reduce to a usual maximum dose of 1 g/day.

OTC labeling (patient-guided therapy): Immediate release: Initial: 200 to 400 mg once, followed by 200 mg every 8 to 12 hours as needed; maximum dose: 400 mg in any 8- to 12-hour period or 600 mg in a 24-hour period.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.

Altered kidney function:

CrCl ≥60 mL/minute: No dosage adjustment necessary (<1% of unchanged drug excreted in the urine) (Anttila 1980; expert opinion).

CrCl >30 to <60 mL/minute: No dosage adjustment necessary (<1% of unchanged drug excreted in the urine) (Anttila 1980; expert opinion). However, use the lowest effective dose for the shortest duration possible. Use of analgesics other than nonsteroidal anti-inflammatory drugs (NSAIDs) or topical NSAIDs may be preferred. Avoid use in patients at high risk for acute kidney injury (ie, volume depleted, hypotensive, elderly, or taking concurrent nephrotoxic medications) (Baker 2020; KDIGO 2013; expert opinion).

CrCl ≤30 mL/minute: Avoid use due to increased risk of acute kidney injury (KDIGO 2013); use of analgesics other than NSAIDs or topical NSAIDs are preferred. However, in select patients where alternatives are not effective, after careful assessment of risks versus benefits, use of naproxen may be considered; use the lowest effective dose for the shortest duration possible with close monitoring of kidney function (expert opinion).

Hemodialysis, intermittent (thrice weekly): Not significantly dialyzable (Davies 1997): Avoid use, as patients with end-stage kidney disease may be at increased risk for bleeding (eg, GI), cardiovascular adverse effects, and loss of residual kidney function (Kurella 2003; expert opinion). However, in select patients after careful assessment of risks versus benefits, use of naproxen may be considered; use the lowest effective dose for the shortest duration possible (Koncicki 2017; expert opinion).

Peritoneal dialysis: Unlikely to be significantly dialyzable (high protein binding): Avoid use, as patients with end-stage kidney disease may be at increased risk for bleeding (eg, GI), cardiovascular adverse effects, and loss of residual kidney function (Kurella 2003; expert opinion). However, in select patients after careful assessment of risks versus benefits, use of naproxen may be considered; use the lowest effective dose for the shortest duration possible (Koncicki 2017; expert opinion).

CRRT: Avoid use (expert opinion).

PIRRT (eg, sustained, low-efficiency diafiltration): Avoid use (expert opinion).

Acute kidney injury while on naproxen therapy: Discontinue use (expert opinion).

Dosing: Hepatic Impairment: Adult

There are no specific dosage adjustments provided in the manufacturer’s labeling; use with caution to avoid adverse effects and discontinue if hepatic function worsens.

Dosing: Pediatric

(For additional information see "Naproxen: Pediatric drug information")

Note: Dosage expressed as naproxen base; 200 mg naproxen base is equivalent to 220 mg naproxen sodium. In pediatric patients, all dosing is for either the immediate-release or controlled-/delayed-release preparations; however, delayed- or controlled-released dosage forms may not be appropriate for use in smaller pediatric patients (eg, calculated dose is less than available dosage forms, patient unable to swallow solid dosage form).

Analgesia/pain, mild to moderate

Analgesia/pain, mild to moderate:

Children and Adolescents <60 kg: Limited data available: Oral: 5 to 7 mg/kg/dose every 8 to 12 hours; maximum daily dose: 1,000 mg/day (Berde 2002; Zeltzer 2020).

Children and Adolescents ≥60 kg: Limited data available: Oral: 5 to 7 mg/kg/dose every 8 to 12 hours; maximum daily dose: 1,000 mg/day (Berde 2002; Zeltzer 2020). Note: Usual adult dose is 500 mg once, followed by 250 to 500 mg every 12 hours as needed or 250 mg every 6 to 8 hours as needed (manufacturer's labeling).

OTC labeling: Children ≥12 years and Adolescents: Immediate release (eg, Aleve): Oral: 200 mg every 8 to 12 hours; if needed may use 400 mg for the initial dose; maximum daily dose: 600 mg/day.

Ankylosing spondylitis

Ankylosing spondylitis: Limited data available: Children and Adolescents: Immediate release, controlled/delayed release: 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 2016; Weiss 2022).

Fever

Fever: OTC labeling: Children ≥12 years and Adolescents: Immediate release (eg, Aleve): Oral: 200 mg every 8 to 12 hours; if needed may use 400 mg for the initial dose; maximum daily dose: 600 mg/day.

Juvenile idiopathic arthritis

Juvenile idiopathic arthritis (JIA):

Note: Scheduled nonsteroidal anti-inflammatory drug (NSAID) therapy may be an appropriate first-line treatment option with or without intraarticular glucocorticoids for certain types of JIA; however, due to adverse effect risks with NSAIDs, therapy should be discontinued if not found beneficial after an adequate trial (ACR [Onel 2022]; ACR [Ringold 2019]). An adequate NSAID trial duration has not been defined in expert recommendations (ACR [Onel 2022]); in clinical trials of NSAIDs for JIA, initial beneficial effects were generally observed within 2 weeks (Ruperto 2005). As initial therapy for polyarticular JIA, NSAID monotherapy should be not initiated over a disease-modifying anti-rheumatic drug (ACR [Ringold 2019]).

Children and Adolescents: Immediate release, controlled/delayed release: Oral: 10 to 15 mg/kg/day in 2 divided doses; maximum daily dose: 1,000 mg/day (Hollingworth 1993; Litalien 2001; Ruperto 2005; Shi 2021).

Migraine, treatment

Migraine, treatment: Limited data available: Children >6 years and Adolescents: Immediate release, controlled/delayed release: Oral: 5 to 7 mg/kg/dose every 8 to 12 hours; maximum daily dose: 1,000 mg/day; dosing based on usual analgesic dosing for naproxen and migraine occurrence (Berde 2002; Géraud 2004; Gunner 2008; Zeltzer 2020). Note: In pediatric patients ≥12 years of age, improved efficacy has been shown using a fixed-dose combination with sumatriptan (Derosier 2012; McDonald 2011; Winner 2015); refer to Sumatriptan and Naproxen monograph for additional information.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Pediatric

Children and Adolescents:

eGFR ≥60 mL/minute/1.73 m2: No dosage adjustment necessary.

eGFR 30 to <60 mL/minute/1.73 m2: There are no specific dosage adjustments provided in the manufacturer's labeling; use with caution and consider using a reduced dose. KDIGO guidelines recommend to temporarily discontinue in patients with intercurrent disease that increases risk of acute kidney injury (KDIGO 2013; manufacturer's labeling).

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

Dosing: Hepatic Impairment: Pediatric

There are no specific dosage adjustments provided in the manufacturer’s labeling; use with caution and consider using a reduced dose.

Dosing: Older Adult

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

Dosage Forms: US

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

Capsule, Oral, as sodium:

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

Generic: 220 mg

Kit, Combination:

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 [scored]

Generic: 250 mg, 375 mg, 500 mg

Tablet, Oral, as sodium:

Aleve: 220 mg [contains fd&c blue #2 (indigo carm) aluminum lake]

All Day Pain Relief: 220 mg [DSC] [contains fd&c blue #2 (indigo carm) aluminum lake]

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

Anaprox DS: 550 mg [scored]

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

GoodSense Naproxen Sodium: 220 mg [gluten free; contains fd&c blue #2 (indigo carm) 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

EC-Naproxen: 375 mg, 500 mg

Generic: 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, 750 mg

Generic Equivalent Available: US

May be product dependent

Dosage Forms Considerations

EnovaRX-Naproxen and Equipto-Naproxen creams are compounded from a kit. Refer to manufacturer’s package insert for compounding instructions.

Naproxen Comfort Pac kit contains naproxen tablets and Duraflex Comfort Gel

Flanax Pain Relief kit contains naproxen tablets and Flanax Liniment

Dosage Forms: Canada

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

Suppository, Rectal:

Generic: 500 mg ([DSC])

Suspension, Oral:

Generic: 125 mg/5 mL (40 mL, 474 mL)

Tablet, Oral:

Generic: 125 mg, 250 mg, 375 mg, 500 mg

Tablet, Oral, as sodium:

Anaprox: 275 mg [contains fd&c blue #2 (indigo carm) aluminum lake]

Anaprox DS: 550 mg [contains fd&c blue #2 (indigo carm) aluminum lake]

Generic: 275 mg, 550 mg

Tablet Delayed Release, Oral:

Naprosyn: 375 mg, 500 mg

Naxen EC: 250 mg, 375 mg, 500 mg

Generic: 250 mg, 375 mg, 500 mg

Tablet Extended Release 24 Hour, Oral:

Naprosyn: 750 mg [contains fd&c yellow #6 (sunset yellow)]

Administration: Adult

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.

Bariatric surgery: Some institutions may have specific protocols that conflict with these recommendations; refer to institutional protocols as appropriate. IR tablet, capsule, caplet, gelcap, oral suspension, and topical power formulations are available. If safety and efficacy can be effectively monitored, no change in formulation or administration is required after bariatric surgery; however, nonsteroidal anti-inflammatory drugs are not recommended for routine use after bariatric surgery. Where possible, use cyclooxygenase-2 selective therapy (celecoxib 100 to 200 mg up to twice a day). If enteric-coated/delayed-release formulations of naproxen are used after bariatric surgery, coadministration with proton pump inhibitor is advisable.

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

Administration: Pediatric

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

Oral suspension: Shake suspension well before use.

Tablets: Do not chew, crush, or break delayed- or controlled-release tablet; swallow whole.

Use: Labeled Indications

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

Dysmenorrhea, primary: Treatment of primary dysmenorrhea. Delayed-release naproxen is not recommended for initial treatment of acute pain.

Pain and/or fever: Relief of mild to moderate pain and/or fever. Delayed-release naproxen is not recommended for initial treatment of acute pain.

Use: Off-Label: Adult

Abnormal uterine bleeding, nonacute; Migraine, acute treatment

Medication Safety Issues
Sound-alike/look-alike issues:

Naproxen may be confused with Natacyn, Nebcin

Anaprox may be confused with Anaspaz, Avapro

Naprelan may be confused with Naprosyn

Naprosyn may be confused with Natacyn, Nebcin

Older Adult: High-Risk Medication:

Beers Criteria: Naproxen is identified in the Beers Criteria as a potentially inappropriate medication to be avoided for chronic use in patients 65 years and older (unless alternative agents ineffective and patient can receive concomitant gastroprotective agent) due to increased risk of GI bleeding and peptic ulcer disease in older adults in high risk category (eg, older than 75 years or receiving concomitant oral/parenteral corticosteroids, anticoagulants, or antiplatelet agents) (Beers Criteria [AGS 2019]).

International issues:

Flogen [Mexico] may be confused with Flovent brand name for fluticasone [US, Canada]

Flogen [Mexico] may be confused with Floxin brand name for flunarizine [Thailand], norfloxacin [South Africa], ofloxacin [US, Canada], and perfloxacin [Philippines]

Adverse Reactions (Significant): Considerations
Cardiovascular effects

Use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with an increased risk of serious adverse cardiovascular (CV) events, including acute myocardial infarction (MI), cerebrovascular accident, and CV death. New-onset hypertension or exacerbation of hypertension may occur with NSAID use which may also contribute to an increased risk of CV events (Ref). New-onset or exacerbation of heart failure may also occur with cyclooxygenase (COX)-2 selective NSAIDs (ie, coxibs) and nonselective NSAIDs, including ibuprofen, resulting in an increased risk of hospitalizations for heart failure and death in patients with heart failure (Ref).

Data collected by the Coxib and traditional NSAID Trialists’ (CNT) Collaborative has shown that high-dose naproxen (1,000 mg daily) may have the most favorable CV risk profile among NSAIDs analyzed (Ref); however, data from the PRECISION trial showed no difference with regards to risk between naproxen, ibuprofen, or celecoxib after a treatment duration of therapy of ~3 years (Ref). Additional trials are also conflicted with regards to the risk of CV events with naproxen as compared to other NSAIDs (Ref). The FDA states that there is insufficient data to determine if risk of myocardial infarction or stroke is definitely higher or lower for any particular NSAID as compared to another (Ref).

Mechanism: Dose- and time-related; inhibition of COX-2 by NSAIDs results in a reduction in the production of prostaglandin I2 (prostacyclin) in the vascular endothelium (Ref); animal studies have shown that reduced prostacyclin activity may result in a predisposition to vascular injury (Ref). In addition, prostaglandins inhibit sodium resorption in the thick ascending loop of Henle and collecting tubule; therefore, a reduction in prostaglandin synthesis by NSAIDs may cause sodium and fluid retention and result in hypertension and decreased efficacy of diuretics (Ref).

Onset: Varied; increased risk may be apparent within the first weeks following initiation of treatment (Ref); longer duration of therapy may further increase risk (Ref).

Risk factors:

• ≥65 years of age

• Higher doses (especially with regards to CV thrombotic risk) (Ref)

• Longer duration of use and frequent use (eg, ≥22 days per month) (Ref)

• Preexisting cardiovascular disease (CVD) or presence of risk factors for CVD, including use following coronary artery bypass graft surgery (Ref)

- Note: Relative risk appears to be similar in those with and without known CVD or risk factors for CVD; however, absolute incidence of serious CV thrombotic events appears to be higher in patients with known CVD or risk factors for CVD due to an increased baseline risk (Ref)

Gastrointestinal events

Use of nonsteroidal anti-inflammatory drugs (NSAIDs), especially nonselective NSAIDs such as naproxen, is associated with an increased risk of serious gastrointestinal (GI) adverse events, including gastrointestinal inflammation, gastrointestinal hemorrhage, gastrointestinal ulcer, and gastrointestinal perforation; severity may range from asymptomatic to fatal (Ref).

Mechanism: Dose- and time-related; inhibition of cyclooxygenase (COX)-1 by NSAIDs results in a reduction in the production of mucosal-protective prostaglandin E2 (Ref).

Onset: Varied; GI events can occur at any time during use and without warning symptoms. A longer duration of use (eg, ≥7 days) (Ref) is associated with a greater risk.

Risk factors:

≥65 years of age (Ref)

Longer duration of use (eg, ≥7 days) (Ref)

Higher doses (Ref)

Prior history of peptic ulcer disease and/or GI bleeding (Ref)

Concomitant use of agents known to increase the risk of GI bleeding (eg, aspirin (Ref), anticoagulants, corticosteroids (Ref), selective serotonin reuptake inhibitors (Ref))

Comorbid Helicobacter pylori infection (Ref)

Advanced liver disease/cirrhosis

Coagulopathy

Smoking

Consumption of alcohol

People with poor general health status

Small intestine damage: Small intestine bacterial overgrowth (SIBO), including SIBO induced by proton pump inhibitor therapy, may be associated with an increased risk of small intestine damage (Ref)

Hematologic effects

Use of nonsteroidal anti-inflammatory drugs (NSAIDs), including naproxen, is associated with prolonged bleeding time and an increased risk for hemorrhage (Ref).

In addition, drug-induced hemolytic anemia may occur (Ref). Rarely, NSAID use has been associated with potentially severe blood dyscrasias (eg, agranulocytosis, aplastic anemia, neutropenia, thrombocytopenia) (Ref).

Mechanism:

Prolonged bleeding time: Inhibition of cyclooxygenase (COX)-1 by nonselective NSAIDs causes a decrease in the production of prostaglandins, prostacyclins, and thromboxanes, including thromboxane A2 (TxA2) (Ref). As a result, patients may exhibit a decrease in platelet adhesion and aggregation and subsequent prolonged bleeding time (Ref).

Blood dyscrasias: Not clearly established; anemia may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis.

Onset:

Prolonged bleeding time: Rapid; suppression of platelet COX-1 activity occurs within hours of administration (Ref). In patients receiving antithrombotic therapy after myocardial infarction, the use of NSAIDs has been associated with an increased risk of bleeding and excess thrombotic events even after short-term treatment (eg, <3 days) (Ref).

Risk factors:

Bleeding events:

- Preexisting coagulation disorders

- Concomitant use of agents known to increase the risk of bleeding (eg, anticoagulants (Ref), antithrombotics (Ref), antiplatelet agents [eg, aspirin], selective serotonin reuptake inhibitors (Ref), or serotonin norepinephrine reuptake inhibitors)

- Use during and immediately following surgical procedures (Ref)

Hepatic effects

Use of nonsteroidal anti-inflammatory drugs (NSAIDs), including naproxen, may result in mild transaminase elevations, especially with higher doses (Ref); rarely, serious hepatocellular injury may result in acute hepatitis (Ref). Severe liver injury requiring liver transplantation has also been reported (Ref). Most cases of liver injury are likely reversible with rapid recovery following discontinuation (Ref).

Mechanism: Not clearly established; may be a result of a toxic metabolite (Ref).

Onset: Varied; reported cases have occurred within 1 to 6 weeks of initiation (Ref).

Risk factors:

• Prior NSAID-related liver injury (Ref)

- Note: Cross-reactivity may occur among propionic acid derivatives (eg, ibuprofen, naproxen, ketoprofen) (Ref)

Hypersensitivity reactions (immediate and delayed)

Hypersensitivity reactions (immediate and delayed) involving the skin (eg, angioedema, urticaria), airways (eg, dyspnea, rhinorrhea) and/or other organs have been reported (Ref). Clinical phenotypes of nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity reactions include NSAID-exacerbated respiratory disease (NERD), NSAID-induced urticaria/angioedema (NIUA), NSAID-exacerbated cutaneous disease (NECD) and single NSAID-induced urticaria/angioedema or anaphylaxis (Ref). Delayed hypersensitivity reactions including drug rash with eosinophilia and systemic symptoms (DRESS) and Stevens-Johnson syndrome (SJS) have also been associated with naproxen (Ref).

Mechanism:

Immediate reactions: Non–dose-related; most reactions (ie, NERD, NECD, NIUA) are non-immunologic related to inhibition of cyclooxygenase-1 (COX-1) with subsequent activation of mast cells and eosinophils causing release of inflammatory mediators including cysteinyl-leukotrienes (cysLTs) (Ref). Some immediate reactions are IgE-mediated (Ref).

Delayed reactions: Delayed hypersensitivity reactions are T-cell–mediated (Ref).

Onset:

Immediate reactions: Rapid; occur within 1 hour of administration but may occur several hours after exposure (Ref).

Delayed reactions (including DRESS and SJS): Varied; generally occurs after 1 to 8 weeks after initiation (Ref), although some patients may develop symptoms within 24 hours (Ref).

Risk factors:

• Presence of chronic rhinosinusitis with nasal polyps, family history of NERD and/or severe asthma may increase the risk of NERD (Ref). The prevalence of NERD in adult patients with asthma is ~10% to 20% (Ref).

• Chronic urticaria increases the risk of NECD (Ref). NSAID-induced reactions are less frequent and less intense when chronic urticaria is in remission or under control (Ref). Approximately 12% to 30% of patients with chronic idiopathic urticaria develop exacerbations of their disease with use of naproxen and other COX-1 inhibitors (Ref).

• Cross-reactivity between aspirin and NSAIDs, including naproxen (with predominant COX-1 inhibition) have been described in patients with a history of NERD, NECD and NIUA (Ref). Cross-reactivity between aspirin/NSAID and acetaminophen, a weak COX inhibitor and between aspirin/NSAID and nonselective COX-2 inhibitors (eg, meloxicam, nimesulide) may occur (Ref). Although selective COX-2 inhibitors (eg, celecoxib, etoricoxib) are generally tolerated in patients with NERD (Ref), cross-reactions may occur especially in patients with histories of urticaria/angioedema (Ref).

• Cross-reactivity may occur among propionic acid derivatives (eg, ibuprofen, naproxen, ketoprofen) in patients with histories of immediate hypersensitivity reactions to naproxen, but tolerance to aspirin (Ref)

Kidney effects

Use of nonsteroidal anti-inflammatory drugs (NSAIDs), including naproxen, is associated with an increased risk of several kidney-specific effects: Hemodynamically-mediated acute kidney injury, interstitial nephritis (with or without nephrotic syndrome), and renal papillary necrosis.

Hemodynamically-mediated acute kidney injury (AKI): Hemodynamically-mediated AKI may occur following use of either cyclooxygenase (COX)-2 selective NSAIDs (ie, coxibs) or nonselective NSAIDs, including naproxen (Ref); the risk may be greater with nonselective NSAIDs, especially indomethacin (Ref). The risk of developing AKI is decreased upon discontinuation (Ref). In patients who develop AKI, kidney function is likely to return to baseline following prompt discontinuation of the offending NSAID and supportive care (Ref); however, the mechanism of the damage and other concurrent factors can contribute to irreversibility.

Acute interstitial nephritis (AIN) with or without nephrotic syndrome: Patients may develop NSAID-associated proteinuria combined with interstitial nephritis and varying degrees of kidney impairment; the “classic triad” of fever, rash, and eosinophilia is less commonly observed in NSAID-associated AIN than with antibiotic-induced AIN (Ref). Kidney histology may reveal minimal change glomerulonephritis or membranous nephropathy (Ref). While use of naproxen has been associated with this clinical picture; the risk may be greatest with fenoprofen as compared to other NSAIDS (Ref). Proteinuria generally improves within weeks following discontinuation; full recovery may require treatment and take up to a year (Ref).

Papillary necrosis: Chronic use of NSAIDs, including naproxen, has resulted in the development of papillary necrosis which may occur in conjunction with chronic interstitial nephritis and progressive decline in glomerular filtration rate as a clinical syndrome known as analgesic nephropathy (Ref). However, controversy exists on the degree to which NSAID use increases the risk for chronic kidney disease and analgesic nephropathy (Ref). Acute papillary necrosis may occur following NSAID overdose, especially in a setting of severe dehydration or intravascular volume depletion (Ref).

Mechanism:

Hemodynamically-mediated AKI: Dose- and time-related; inhibition of cyclooxygenase (COX)-1 and COX-2 by NSAIDs results in a reduced production of nephroprotective prostaglandins and subsequent attenuation of renal vasodilation (Ref). In addition, an increase in vasoconstriction of the afferent arteriole and impaired renal blood flow causes a reduction in the glomerular capillary pressure and filtration (Ref).

AIN with or without nephrotic syndrome: Not clearly established. Following inhibition of COX-1 and COX-2 by NSAIDs, arachidonic acid is formed which may be further metabolized to leukotrienes via the lipoxygenase pathway; leukotrienes may increase vascular permeability within glomerular capillaries and peritubular capillaries and increase lymphocyte recruitment and activation (Ref).

Papillary necrosis: Time-related; exact mechanism is not clearly established; may be due to direct toxicity and/or inhibition of prostaglandin-mediated vasodilation resulting in ischemic necrosis (Ref).

Onset:

AKI: Rapid; may occur within days of treatment initiation (Ref)

AIN with or without nephrotic syndrome: Varied; mean time of onset of ~5 months (range: 2 weeks to 18 months) has been described (Ref).

Risk factors:

• AKI:

- Preexisting kidney impairment

- Chronic kidney disease

• Note: High cumulative doses (eg, ibuprofen >300 mg/day) may increase the risk for progression of chronic kidney disease (Ref)

- ≥65 years of age (Ref)

Note: NSAID-associated AKI may also occur in pediatric patients, even at therapeutic doses (Ref)

• Hemodynamically-mediated AKI:

- Preexisting conditions which result in decreased effective arterial circulation (ie, conditions where renal blood flow/renal perfusion may be dependent on prostaglandin-mediated vasodilation) (Ref):

Volume depletion (eg, due to concomitant diuretic use, nausea, or vomiting)

Heart failure (Ref)

Cirrhosis and ascites (Ref)

Nephrotic syndrome

- Concomitant use of diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or calcineurin inhibitors (Ref)

• AIN with or without nephrotic syndrome: Prior history of NSAID-induced nephrotic syndrome; recurrence has been described (Ref)

• Papillary necrosis (acute):

- Massive NSAID ingestion (Ref)

- Dehydration (Ref)

- Intravascular volume depletion (Ref)

• Papillary necrosis (chronic)/analgesic nephropathy: Chronic concomitant use of other analgesics (eg, aspirin, acetaminophen) (Ref)

Pseudoporphyria

Pseudoporphyria including erythema, skin fragility, blistering, and scarring in sun-exposed skin has been reported in adult and pediatric patients (Howard 1985, Wallace 1994); children with juvenile idiopathic arthritis (JIA) appear to be at an increased risk with a reported incidence of 10% to 12% (De Silva 2000, Lang 1994). Sun-exposed areas of the body are more commonly affected and include the dorsal aspect of the hands, the face, and the extensor surfaces of the legs (Frank 2018, Lang 1994). Time to resolution of the rash in children with JIA is variable (median: 21 days [range: 4 days to 6 weeks]); facial scarring can be disfiguring and may be persistent (DeSilva 2000, Lang 1994).

Mechanism: Unknown; hypothesized to be a nonimmune-mediated phototoxic effect resulting in cell membrane damage (Lang 1994). This, although, does not seem to be the only contributing factor, as pseudoporphyria has been reported in climates with low levels of sunshine (De Silva 2000).

Onset: Varied; duration of treatment with naproxen and the development of pseudoporphyria is not well reported (Howard 1985, Wallace 1994). One pediatric study included only patients receiving naproxen treatment for ≥4 weeks with a median onset of 11 months (range: 1 month to 18 months) (De Silva 2000).

Risk factors:

• Age <18 years (Lang 1994)

• Comorbid JIA (Lang 1994)

• Fair skin (De Silva 2000)

• Blue/gray eyes (De Silva 2000)

• Ultraviolet A (UVA) exposure (eg sun exposure, tanning bed use) (Frank 2018, De Silva 2000)

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

>10%:

Gastrointestinal: Dyspepsia (≤14%)

Nervous system: Headache (3% to 15%)

1% to 10%:

Cardiovascular: Chest pain (<3%), edema (≤9%), hypertension (<3%; including exacerbation of hypertension), palpitations (<3%), peripheral edema (<3%)

Dermatologic: Diaphoresis (<3%), ecchymoses (≤9%), pruritus (≤9%), skin rash (≤9%)

Endocrine & metabolic: Hyperglycemia (<3%), increased thirst (<3%)

Gastrointestinal: Abdominal pain (3% to 9%), constipation (3% to 9%), diarrhea (≤9%), dysphagia (<3%), flatulence (<3%), gastritis (<3%), gastrointestinal hemorrhage, gastrointestinal perforation, gastrointestinal ulcer (including gastric ulcer and esophageal ulcer), heartburn (3% to 9%), nausea (3% to 9%), stomatitis (<3%; including oral mucosal ulcer), vomiting (<3%)

Genitourinary: Cystitis (<3%), urinary tract infection (3% to 9%)

Hematologic & oncologic: Anemia (<3%), purpuric disease (<3%)

Infection: Infection (3% to 9%)

Nervous system: Dizziness (≤9%), drowsiness (3% to 9%), insomnia (<3%), pain (3% to 9%), paresthesia (<3%), vertigo (<3%)

Neuromuscular & skeletal: Arthralgia (<3%), arthropathy (<3%), asthenia (<3%), back pain (3% to 9%), lower limb cramp (<3%), myalgia (<3%), tendinopathy (<3%; including fibrotendinitis)

Ophthalmic: Visual disturbance (<3%)

Otic: Auditory disturbance (<3%; including auditory impairment and deafness), tinnitus (3% to 9%)

Respiratory: Bronchitis (<3%), dyspnea (≤9%), flu-like symptoms (10%), increased cough (<3%), pharyngitis (3% to 9%), rhinitis (3% to 9%), sinusitis (3% to 9%)

Miscellaneous: Fever (<3%)

<1%:

Cardiovascular: Acute myocardial infarction, angina pectoris, aortic valve stenosis, bundle branch block, cardiac arrhythmia, coronary artery disease, deep vein thrombosis, ECG abnormality, heart failure, right heart failure, subdural hematoma, syncope, tachycardia, vasculitis, vasodilation

Dermatologic: Acne vulgaris, alopecia, bullous skin disease, cellulitis, contact dermatitis, dermal ulcer, eczema, epidermolysis bullosa, erythema multiforme, erythema nodosum, herpes simplex dermatitis, lichen planus, nail disease, photodermatitis, pustular rash, skin necrosis, skin photosensitivity, Stevens-Johnson syndrome, subcutaneous nodule, toxic epidermal necrolysis, urticaria, vasculitis of the skin, xeroderma

Endocrine & metabolic: Albuminuria, alkalosis, decreased glucose tolerance, dehydration, glycosuria, hypercholesteremia, hyperkalemia, hyperuricemia, hypoglycemia, hypokalemia, menstrual disease, porphyria cutanea tarda, weight loss

Gastrointestinal: Abdominal distention, anorexia, aphthous stomatitis, cholecystitis, cholelithiasis, colitis, eructation, esophageal achalasia, esophagitis, exacerbation of Crohn's disease, exacerbation of ulcerative colitis, gastroenteritis, gastrointestinal candidiasis, gastrointestinal inflammation, gastrointestinal necrosis, gastrointestinal obstruction, hematemesis, melena, mucous membrane abnormality, pancreatitis, periodontal abscess

Genitourinary: Dysmenorrhea, dysuria, hematuria, infertility, nephrotic syndrome, nocturia, pelvic pain, prostatic disease, pyuria, urinary frequency, urinary incontinence, urinary retention, uterine hemorrhage, uterine spasm, vaginitis

Hematologic & oncologic: Agranulocytosis, aplastic anemia, eosinophilia, granulocytopenia, hemolytic anemia (Garratty 2014), hemorrhage, neutropenia (Strom 1993), prolonged bleeding time, rectal hemorrhage, thrombocytopenia (Sahu 2020)

Hepatic: Hepatitis, hepatosplenomegaly, increased serum alanine aminotransferase, increased serum aspartate aminotransferase, jaundice

Hypersensitivity: Angioedema, fixed drug eruption, hypersensitivity reaction, nonimmune anaphylaxis

Infection: Abscess, herpes zoster infection

Nervous system: Abnormal dreams, amnesia, anxiety, aseptic meningitis, ataxia, chills, cognitive dysfunction, confusion, depression, emotional lability, hypertonia, lack of concentration, malaise, migraine, myasthenia, nervousness, neuralgia, neuritis, paralysis, seizure

Neuromuscular & skeletal: Bone fracture, bursitis, Lambert-Eaton syndrome, neck pain, neck stiffness, ostealgia, systemic lupus erythematosus

Ophthalmic: Abnormal lacrimation, amblyopia, blepharoptosis, cataract, conjunctivitis, corneal opacity, diplopia, eye pain, keratoconjunctivitis, optic neuritis (including retrobulbar), optic papillitis, papilledema, scleritis

Otic: Otitis media

Renal: Glomerulonephritis, increased blood urea nitrogen, increased serum creatine, interstitial nephritis, nephrolithiasis, pyelonephritis, renal disease (nephrosclerosis), renal failure syndrome, renal pain, renal papillary necrosis

Respiratory: Asthma, eosinophilic pneumonitis, epistaxis, laryngitis, pneumonia, pulmonary edema, respiratory distress

Frequency not defined: Cardiovascular: Coronary thrombosis

Postmarketing:

Cardiovascular: Cerebrovascular accident (FDA 2015)

Endocrine & metabolic: Pseudoporphyria (Lang 1994)

Hepatic: Hepatotoxicity (idiosyncratic) (Chalasani 2021)

Immunologic: Drug reaction with eosinophilia and systemic symptoms (Guerrero Gómez 2020)

Renal: Acute kidney injury (Rahman 2014)

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).

Warnings/Precautions

Concerns related to adverse effects:

• CNS effects: May cause drowsiness, dizziness, blurred vision, and other neurologic effects that may impair physical or mental abilities; patients must be cautioned about performing tasks that 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.

• Hyperkalemia: NSAID use may increase the risk of hyperkalemia, particularly in patients ≥65 years of age, in patients with diabetes or renal disease, and with concomitant use of other agents capable of inducing hyperkalemia (eg, ACE-inhibitors). Monitor potassium closely.

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 2016a; Horsley 2019; Thorell 2016).

• Hepatic impairment: Use with caution in patients with hepatic impairment.

• Renal impairment: Use with caution in patients with renal impairment.

Special populations:

• 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 BP, heart or kidney disease, other serious medical problems, are currently taking a diuretic, anticoagulant, other NSAIDs, or are ≥60 years of age. Do not exceed recommended dosages and duration, 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.

Warnings: Additional Pediatric Considerations

Macrophage activation syndrome has been observed in children and adolescents diagnosed with systemic juvenile idiopathic arthritis on daily nonsteroidal anti-inflammatory drug therapy for extended periods of time; causality not established (Sawhney 2001; Stéphan 2001).

Metabolism/Transport Effects

Substrate of CYP1A2 (minor), CYP2C9 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

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

Abrocitinib: Agents with Antiplatelet Properties may enhance the antiplatelet effect of Abrocitinib. Management: Do not use antiplatelet drugs with abrocitinib during the first 3 months of abrocitinib therapy. The abrocitinib prescribing information lists this combination as contraindicated. This does not apply to low dose aspirin (81 mg/day or less). Risk X: Avoid combination

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

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

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

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

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

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

Antacids: May decrease the absorption of Naproxen. Risk X: Avoid combination

Anticoagulants: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants. Risk C: 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. Management: A comprehensive risk to benefit assessment should be done for all patients before any concurrent use of apixaban and naproxen. If combined, monitor patients extra closely for signs and symptoms of bleeding. Risk D: 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. Risk D: 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. Risk D: Consider therapy modification

Beta-Blockers: Nonsteroidal Anti-Inflammatory Agents may diminish the antihypertensive effect of Beta-Blockers. Risk C: Monitor therapy

Bile Acid Sequestrants: May decrease the absorption of Nonsteroidal Anti-Inflammatory Agents. Risk C: Monitor therapy

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. Risk C: Monitor therapy

Caplacizumab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Caplacizumab. Specifically, the risk of bleeding may be increased. Management: Avoid coadministration of caplacizumab with antiplatelets if possible. If coadministration is required, monitor closely for signs and symptoms of bleeding. Interrupt use of caplacizumab if clinically significant bleeding occurs. Risk D: Consider therapy modification

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

Corticosteroids (Systemic): May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents (Nonselective). Risk C: 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. Risk D: 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. Risk D: Consider therapy modification

Dasatinib: May enhance the anticoagulant effect of Agents with Antiplatelet Properties. Risk C: 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. Risk C: 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. Risk C: Monitor therapy

Desmopressin: Nonsteroidal Anti-Inflammatory Agents may enhance the hyponatremic effect of Desmopressin. Risk C: Monitor therapy

Diflunisal: May enhance the adverse/toxic effect of Naproxen. Specifically, the risk for gastrointestinal toxicity may be increased. Diflunisal may enhance the antiplatelet effect of Naproxen. Diflunisal may decrease the excretion of Naproxen. Risk X: Avoid combination

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

Drospirenone-Containing Products: May enhance the hyperkalemic effect of Nonsteroidal Anti-Inflammatory Agents. Risk C: 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. Risk D: 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. Risk D: 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. Risk D: 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. Risk C: 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. Risk D: 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. Risk D: Consider therapy modification

Herbal Products with Anticoagulant/Antiplatelet Effects (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Bleeding may occur. Risk C: Monitor therapy

Herbal Products with Anticoagulant/Antiplatelet Effects (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Bleeding may occur. Risk C: Monitor therapy

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

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

Icosapent Ethyl: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

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

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

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

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

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

Lithium: Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of Lithium. Management: Consider reducing the lithium dose when initiating a NSAID. Monitor for increased lithium therapeutic/toxic effects if a NSAID is initiated/dose increased, or decreased effects if a NSAID is discontinued/dose decreased. Risk D: 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. Risk D: Consider therapy modification

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

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

Methotrexate: Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of Methotrexate. Management: Avoid coadministration of higher dose methotrexate (such as that used for the treatment of oncologic conditions) and NSAIDs. Use caution if coadministering lower dose methotrexate and NSAIDs. Risk D: Consider therapy modification

Methoxsalen (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Methoxsalen (Systemic). Risk C: Monitor therapy

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

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

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

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

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

Nonsteroidal Anti-Inflammatory Agents: May enhance the adverse/toxic effect of other Nonsteroidal Anti-Inflammatory Agents. Specifically, the risk for gastrointestinal toxicity is increased. Risk X: Avoid combination

Nonsteroidal Anti-Inflammatory Agents (Topical): May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Specifically, the risk of gastrointestinal (GI) toxicity is increased. Management: Coadministration of systemic nonsteroidal anti-inflammatory drugs (NSAIDs) and topical NSAIDs is not recommended. If systemic NSAIDs and topical NSAIDs, ensure the benefits outweigh the risks and monitor for increased NSAID toxicities. Risk D: Consider therapy modification

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

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

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. Risk C: Monitor therapy

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

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

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

Potassium Salts: Nonsteroidal Anti-Inflammatory Agents may enhance the hyperkalemic effect of Potassium Salts. Risk C: 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. Risk C: 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: Avoid coadministration of pralatrexate with nonsteroidal anti-inflammatory drugs (NSAIDs). If coadministration cannot be avoided, closely monitor for increased pralatrexate serum levels or toxicity. Risk D: Consider therapy modification

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

Prostacyclin Analogues: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: 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). Risk C: 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. Risk C: 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. Risk D: 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). Management: Nonselective NSAIDs may reduce aspirin's cardioprotective effects. Administer ibuprofen 30-120 minutes after immediate-release aspirin, 2 to 4 hours after extended-release aspirin, or 8 hours before aspirin. Risk D: Consider therapy modification

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. Risk D: Consider therapy modification

Selumetinib: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: Monitor therapy

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

Sucralfate: May decrease the absorption of Naproxen. Risk X: Avoid combination

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

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 due to a potential risk of acute renal failure. Diclofenac appears to confer the most risk. Risk D: Consider therapy modification

Tenoxicam: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Risk X: 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. Risk C: Monitor therapy

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

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

Tricyclic Antidepressants: May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents. Specifically, the risk of major adverse cardiac events (MACE), hemorrhagic stroke, ischemic stroke, and heart failure may be increased. Tricyclic Antidepressants may enhance the antiplatelet effect of Nonsteroidal Anti-Inflammatory Agents. Risk C: Monitor therapy

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

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

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

Vitamin E (Systemic): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Risk C: 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. Risk D: Consider therapy modification

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

Food Interactions

Naproxen absorption rate/levels may be decreased if taken with food. Management: Administer with food, milk, or antacids to decrease GI adverse effects.

Reproductive Considerations

Nonsteroidal anti-inflammatory drugs (NSAIDs) may delay or prevent rupture of ovarian follicles. This may be associated with infertility that is reversible upon discontinuation of the medication. Consider discontinuing use in patients having difficulty conceiving or those undergoing investigation of fertility. In an observational study of couples planning a pregnancy, doses of naproxen <1,500 mg within the previous 4 weeks were not associated with a reduced probability of becoming pregnant (McInerney 2017).

In an observational study of couples planning a pregnancy, cumulative doses of naproxen <3,000 mg consumed by the male within the previous 4 weeks did not decrease the probability of fathering a child. Cumulative doses of naproxen ≥3,000 mg within the previous 4 weeks may decrease the probability of fathering a child; however, this was based on a limited number of patients and the results were imprecise (Wesselink 2020). Based on available information, NSAIDs can be continued in males with rheumatic and musculoskeletal diseases who are planning to father a child (ACR [Sammaritano 2020]).

Pregnancy Considerations

Naproxen crosses the placenta (Brogden 1975; Siu 2002).

The use of nonsteroidal anti-inflammatory drugs (NSAIDs) close to conception may be associated with an increased risk of miscarriage due to cyclooxygenase-2 inhibition interfering with implantation (Bermas 2014; Bloor 2013).

Birth defects have been observed following in utero NSAID exposure in some studies; however, data are 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 (Bermas 2014; Bloor 2013). Maternal NSAID use may cause fetal renal dysfunction leading to oligohydramnios. Although rare, this may occur as early as 20 weeks' gestation and is more likely to occur with prolonged maternal use. Oligohydramnios may be reversible following discontinuation of the NSAID (Dathe 2019; FDA 2020). In addition, nonclosure of the ductus arteriosus postnatally may occur and be resistant to medical management (Bermas 2014; Bloor 2013).

Avoid maternal use of NSAIDs beginning at 20 weeks' gestation. If NSAID use is necessary between 20 and 30 weeks' gestation, limit use to the lowest effective dose and shortest duration possible; consider ultrasound monitoring of amniotic fluid if treatment extends beyond 48 hours and discontinue the NSAID if oligohydramnios is found (FDA 2020). Because NSAIDs may cause premature closure of the ductus arteriosus, product labeling for naproxen specifically states to avoid use starting at 30 weeks' gestation.

Based on available information, NSAIDs can be continued during the first 2 trimesters of pregnancy in patients with rheumatic and musculoskeletal diseases; use in the third trimester is not recommended (ACR [Sammaritano 2020]).

NSAIDs may be used as part of a multimodal approach to pain relief following cesarean delivery (ACOG 2019).

NSAIDs are not preferred for the acute management of migraine during pregnancy (Burch 2020; van Casteren 2020). However, use of naproxen during the second trimester may be considered when an NSAID is required (Burch 2020).

Breastfeeding Considerations

Naproxen is present in breast milk.

The relative infant dose (RID) of naproxen is 3.3% when calculated using the highest breast milk concentration located and compared to a weight-adjusted maternal dose of 750 mg/day.

In general, breastfeeding is considered acceptable when the RID is <10% (Anderson 2016; Ito 2000).

The RID of naproxen was calculated using a breast milk concentration of 2.37 mcg/mL, providing an estimated infant dose via breast milk of 0.36 mg/kg/day. This milk concentration was obtained following maternal administration of oral naproxen 375 mg twice daily for 3 weeks to 1 woman ~6 months postpartum. Naproxen was detected in the urine of the breastfeeding infant. The cumulative amount of naproxen found in the urine of the infant was 0.26% of the cumulative maternal urinary excretion (Jamali 1982; Jamali 1983).

In a study which included 20 mother-infant pairs, there were 2 cases of drowsiness and 1 case of vomiting in the breastfed infants (Ito 1993).

Nonopioid analgesics, including nonsteroidal anti-inflammatory drugs (NSAIDs), are preferred for breastfeeding patients who require pain control peripartum or for surgery outside of the postpartum period. Short-term use of naproxen is acceptable, but avoid long-term use (>1 week) in breastfeeding patients (ABM [Martin 2018]; ABM [Reece-Stremtan 2017]). NSAIDs are considered compatible for the treatment of rheumatic and musculoskeletal diseases, as well as the management of acute migraine in lactating patients; however, avoid use of naproxen due to its longer half-life (ACR [Sammaritano 2020]; van Casteren 2020).

According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother. Avoid maternal use of NSAIDs if the breastfeeding infant has platelet dysfunction, thrombocytopenia, or a ductal-dependent cardiac lesion (ABM [Martin 2018]; ABM [Reece-Stremtan 2017]; Bloor 2013).

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.

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), LFTs, renal function tests (urine output, serum BUN and creatinine), BP (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, especially in patients with coagulation disorders or who are receiving anticoagulants); monitor for anemia with long-term therapy; monitor for signs/symptoms of immediate or delayed hypersensitivity reactions.

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

Onset of action: Analgesic: 30 to 60 minutes

Duration: Analgesic: <12 hours

Absorption: Oral: Almost 100%

Distribution: 0.16 L/kg

Protein binding: >99% to albumin; increased free fraction in elderly

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

Bioavailability: 95%

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)

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

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

Pharmacokinetics: Additional Considerations

Altered kidney function: Metabolites and conjugates may accumulate.

Pricing: US

Capsules (Aleve Oral)

220 mg (per each): $0.13

Capsules (Naproxen Sodium Oral)

220 mg (per each): $0.34

Suspension (Naprosyn Oral)

125 mg/5 mL (per mL): $2.66

Suspension (Naproxen Oral)

125 mg/5 mL (per mL): $2.39

Tablet, 24-hour (Naprelan Oral)

375 mg (per each): $26.14

500 mg (per each): $23.94

750 mg (per each): $27.71

Tablet, 24-hour (Naproxen Sodium ER Oral)

375 mg (per each): $21.42 - $21.55

500 mg (per each): $21.52 - $21.55

750 mg (per each): $24.66 - $26.32

Tablet, EC (EC-Naprosyn Oral)

375 mg (per each): $5.74

500 mg (per each): $7.01

Tablet, EC (Naproxen Oral)

375 mg (per each): $1.06 - $6.88

500 mg (per each): $1.30 - $8.41

Tablets (Aleve Oral)

220 mg (per each): $0.12

Tablets (Anaprox DS Oral)

550 mg (per each): $11.64

Tablets (Mediproxen Oral)

220 mg (per each): $0.18

Tablets (Naprosyn Oral)

500 mg (per each): $7.42

Tablets (Naproxen Oral)

250 mg (per each): $0.08 - $0.81

375 mg (per each): $0.11 - $1.10

500 mg (per each): $0.13 - $2.79

Tablets (Naproxen Sodium Oral)

220 mg (per each): $0.08 - $0.11

275 mg (per each): $2.29

550 mg (per each): $3.56 - $3.57

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Brand Names: International
  • Aleve (AT, BH, DE, EE, HU, LU, NL, PL, PY, SG, UY);
  • Algezir (RU);
  • Anaflex (BD);
  • Antalgin (ES);
  • Antalnox (FI);
  • Apranax (CR, DO, FR, GT, HN, HU, LU, NI, PA, RU, SV, VN);
  • Aprelax (PH);
  • Apronax (EC);
  • Artagen (IN);
  • Bei Li (CN);
  • Bonyl (DK);
  • Bumaflex N (PY);
  • Cefecon N (UA);
  • Clerinax (PY);
  • Crysanal (AU);
  • Emox (LV);
  • Emoxen (CZ);
  • Flanax (BR, EC);
  • Floginax (IT);
  • Inza (AU, HK);
  • Iraxen (PE);
  • Laser (IT);
  • Licorax (KR);
  • Lundiran (ES);
  • Mobilon (EG);
  • Momen (ES);
  • Momendol (MT);
  • Mox (AR);
  • Myoprox (EG);
  • Nadolex (VE);
  • Nafasol (ZA);
  • Naflax (PH);
  • Naldorex (RO);
  • Nalgedol (LV);
  • Nalgesin (BG, CZ, HR, LV, RU, UA);
  • Naposin (TW);
  • Napoxen (PH);
  • Napren E (NO);
  • Naprex (PK);
  • Naprium (AE, BF, BJ, CI, CY, ET, GH, GM, GN, IQ, IR, JO, KE, LR, LY, MA, ML, MR, MU, MW, NE, NG, OM, SA, SC, SD, SL, SN, SY, TN, TZ, UG, YE, ZM);
  • Naprius (IT);
  • Napro (LK);
  • Napro A (BD);
  • Naprocet (PT);
  • Naprodil (MX);
  • Naproff (UA);
  • Naproflex (TH);
  • Napronax (BR);
  • Naprontag (AR);
  • Naproplat (ZW);
  • Naprorex (AE, CY, IQ, IR, JO, LY, MT, OM, SA, SY, TR, YE);
  • Naproscript (ET, ZW);
  • Naprosyn (AE, AU, BB, BF, BJ, BM, BS, BZ, CI, CY, EC, EG, ES, ET, FI, GB, GH, GM, GN, GR, GY, HU, IE, IN, IQ, IR, IT, JM, JO, KE, LR, LY, MA, ML, MR, MT, MU, MW, NE, NG, OM, PE, PT, PY, QA, SA, SC, SD, SE, SL, SN, SR, SY, TN, TT, TZ, UG, YE, ZM);
  • Naprosyn LE (TH);
  • Naprosyn LLE Forte (PH);
  • Naprosyn SR (AU);
  • Naprosyne (BE, FR, LU);
  • Naprox (LK, QA);
  • Naproxavi (NL);
  • Naproxen (DE);
  • Naprux (AR);
  • Naxen (LK, MX, NZ);
  • Naxen F (KR);
  • Naxen-F CR (KR);
  • Naxene (TH);
  • Naxopren (FI);
  • Naxyn 250 (IL);
  • Naxyn 500 (IL);
  • Noflam (NZ);
  • Noken (JO);
  • Nopain (KW, LB, QA);
  • Nopen (PH);
  • Norane (VE);
  • Norswel (BF, BJ, CI, ET, GH, GM, GN, KE, LR, MA, ML, MR, MU, MW, NE, NG, SC, SD, SL, SN, TN, TZ, UG, ZM);
  • Novaxen (MX);
  • Nycopren (AT, FI);
  • Pairox (BD);
  • Penles (PH);
  • Prexan (IT);
  • Priaxen (BF, BJ, BM, BS, BZ, CI, ET, GH, GM, GN, GY, JM, KE, LR, MA, ML, MR, MU, MW, NE, NG, SC, SD, SL, SN, SR, TN, TR, TT, TZ, UG, ZM);
  • Prodexin (AE, CY, IQ, IR, JO, LY, OM, SA, SY, YE);
  • Progend (BD);
  • Proken (AE, JO, LB, QA, SA);
  • Pronaxen (SE);
  • Pronoflex (VE);
  • Propain (VN);
  • Proxan (NO);
  • Proxen (AE, AT, BH, CH, CY, IQ, IR, JO, LY, OM, QA, SA, SY, TW, VN, YE);
  • Proxidol D.S. (QA);
  • Reuxen (PT, RO);
  • Safrosyn S (MY);
  • Sarimax (PH);
  • Seladin (MY, SG);
  • Sindolan (EC);
  • Snofin (HK);
  • Soden (SG);
  • Sonap (TH);
  • Sutolin (TW);
  • Synflex (AU);
  • Tormax (LK);
  • U-Ritis (TW);
  • Ultranax (BD);
  • Vadaxena (VN);
  • Vimovo (NO);
  • Xenar (IT);
  • Xenifar (ID);
  • Xynap (LK)


For country code abbreviations (show table)
  1. 2019 American Geriatrics Society Beers Criteria Update Expert Panel. American Geriatrics Society 2019 updated AGS Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. J Am Geriatr Soc. 2019;67(4):674-694. doi:10.1111/jgs.15767 [PubMed 30693946]
  2. Abraham NS, Hlatky MA, Antman EM, et al; ACCF/ACG/AHA. ACCF/ACG/AHA 2010 expert consensus document on the concomitant use of proton pump inhibitors and thienopyridines: a focused update of the ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents. Circulation. 2010;122(24):2619-2633. doi:10.1161/CIR.0b013e318202f701 [PubMed 21060077]
  3. Abraham PA, Keane WF. Glomerular and interstitial disease induced by nonsteroidal anti-inflammatory drugs. Am J Nephrol. 1984;4(1):1-6. doi:10.1159/000166764 [PubMed 6731494]
  4. Aleve caplets (naproxen) [prescribing information]. Bayer Healthcare; May 2014.
  5. Aleve liquid gels (naproxen) [prescribing information]. Bayer Healthcare; January 2015.
  6. Aleve tablets (naproxen) [prescribing information]. Bayer Healthcare; May 2014.
  7. Aleve tablets (naproxen) [prescribing information]. Whippany, NJ: Bayer; received 2020.
  8. Alqahtani Z, Jamali F. Clinical outcomes of aspirin interaction with other non-steroidal anti-inflammatory drugs: a systematic review. J Pharm Pharm Sci. 2018;21(1s):29854. doi:10.18433/jpps29854 [PubMed 29891025]
  9. Alun-Jones E, Williams J. Hyponatremia and Fluid Retention in a Neonate Associated With Maternal Naproxen Overdosage. J Toxicol Clin Toxicol. 1986;24(3):257-260. [PubMed 3723650]
  10. American College of Obstetricians and Gynecologists (ACOG) Committee on Practice Bulletins—Obstetrics. ACOG Practice Bulletin No. 209: Obstetric analgesia and anesthesia. Obstet Gynecol. 2019;133(3):e208-e225. doi:10.1097/AOG.0000000000003132 [PubMed 30801474]
  11. American Pain Society (APS). Principles of Analgesic Use in the Treatment of Acute Pain and Cancer Pain. 7th ed. Glenview, IL: 2016.
  12. Anaprox and Anaprox DS (naproxen sodium) [product monograph]. Brantford, Ontario, Canada: Methapharm Inc; January 2022.
  13. Anderson PO, Sauberan JB. Modeling drug passage into human milk. Clin Pharmacol Ther. 2016;100(1):42-52. [PubMed 27060684]
  14. Andersson PG, Hinge HH, Johansen O, Andersen CU, Lademann A, Gøtzsche PC. Double-blind study of naproxen vs placebo in the treatment of acute migraine attacks. Cephalgia. 1989;9(1):29-32. [PubMed 2650879]
  15. Andrejak M, Davion T, Gineston JL, Capron JP. Cross hepatotoxicity between non-steroidal anti-inflammatory drugs. Br Med J (Clin Res Ed). 1987;295(6591):180-181. doi:10.1136/bmj.295.6591.180 [PubMed 3115366]
  16. Anglin R, Yuan Y, Moayyedi P, Tse F, Armstrong D, Leontiadis GI. Risk of upper gastrointestinal bleeding with selective serotonin reuptake inhibitors with or without concurrent nonsteroidal anti-inflammatory use: a systematic review and meta-analysis. Am J Gastroenterol. 2014;109(6):811-819. doi:10.1038/ajg.2014.82 [PubMed 24777151]
  17. Anttila M, Haataja M, Kasanen A. Pharmacokinetics of naproxen in subjects with normal and impaired renal function. Eur J Clin Pharmacol. 1980;18(3):263-268. doi:10.1007/BF00563009 [PubMed 7439246]
  18. Aranda JV, Thomas R. Systematic review: intravenous Ibuprofen in preterm newborns. Semin Perinatol. 2006;30(3):114-120. doi:10.1053/j.semperi.2006.04.003 [PubMed 16813969]
  19. Baker M, Perazella MA. NSAIDs in CKD: Are They Safe? Am J Kidney Dis. 2020;76(4):546-557. doi:10.1053/j.ajkd.2020.03.023 [PubMed 32479922]
  20. Battistella M, Mamdami MM, Juurlink DN, Rabeneck L, Laupacis A. Risk of upper gastrointestinal hemorrhage in warfarin users treated with nonselective NSAIDs or COX-2 inhibitors. Arch Intern Med. 2005;165(2):189-192. doi:10.1001/archinte.165.2.189 [PubMed 15668365]
  21. Becker MA. Treatment of gout flares. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed November 5, 2018.
  22. Bell AD, Roussin A, Cartier R, et al. The Use of Antiplatelet Therapy in the Outpatient Setting: Canadian Cardiovascular Society Guidelines. Can J Cardiol. 2011;27(suppl A):1-59. [PubMed 21640290]
  23. Berde CB, Sethna NF. Analgesics for the treatment of pain in children. N Engl J Med. 2002;347(14):1094-1103. [PubMed 12362012]
  24. Bermas BL. Non-steroidal anti inflammatory drugs, glucocorticoids and disease modifying anti-rheumatic drugs for the management of rheumatoid arthritis before and during pregnancy. Curr Opin Rheumatol. 2014;26(3):334-340. doi:10.1097/BOR.0000000000000054 [PubMed 24663106]
  25. Bhala N, Emberson J, et al. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet. 2013;382(9894):769-779. doi:10.1016/S0140-6736(13)60900-9 [PubMed 23726390]
  26. Bhangu A, Singh P, Fitzgerald JE, Slesser A, Tekkis P. Postoperative nonsteroidal anti-inflammatory drugs and risk of anastomotic leak: meta-analysis of clinical and experimental studies. World J Surg. 2014;38(9):2247-2257. doi:10.1007/s00268-014-2531-1 [PubMed 24682313]
  27. Bhatt DL, Scheiman J, Abraham NS, et al; American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. Circulation. 2008a;118(18):1894-1909. doi:10.1161/CIRCULATIONAHA.108.191087 [PubMed 18836135]
  28. Bhatt DL, Scheiman J, Abraham NS, et al. ACCF/ACG/AHA 2008 Expert Consensus Document on Reducing the Gastrointestinal Risk of Antiplatelet Therapy and NSAID Use. A Report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol. 2008b;52(18):1502-1517. [PubMed 19017521]
  29. Bhave G, Neilson EG. Volume depletion versus dehydration: how understanding the difference can guide therapy. Am J Kidney Dis. 2011;58(2):302-309. doi:10.1053/j.ajkd.2011.02.395 [PubMed 21705120]
  30. Biggins SW, Angeli P, Garcia-Tsao G, et al. Diagnosis, evaluation, and management of ascites, spontaneous bacterial peritonitis and hepatorenal syndrome: 2021 practice guidance by the American Association for the Study of Liver Diseases. Hepatology. 2021;74(2):1014-1048. doi:10.1002/hep.31884 [PubMed 33942342]
  31. Blanca-López N, Pérez-Alzate D, Andreu I, et al. Immediate hypersensitivity reactions to ibuprofen and other arylpropionic acid derivatives. Allergy. 2016;71(7):1048-1056. doi:10.1111/all.12855 [PubMed 26841325]
  32. Bloor M, Paech M. Nonsteroidal anti-inflammatory drugs during pregnancy and the initiation of lactation. Anesth Analg. 2013;116(5):1063-1075. [PubMed 23558845]
  33. Blumenthal KG, Peter JG, Trubiano JA, Phillips EJ. Antibiotic allergy. Lancet. 2019;393(10167):183-198. doi:10.1016/S0140-6736(18)32218-9 [PubMed 30558872]
  34. Bofill Rodriguez M, Lethaby A, Farquhar C. Non-steroidal anti-inflammatory drugs for heavy menstrual bleeding. Cochrane Database Syst Rev. 2019;9(9):CD000400. doi:10.1002/14651858.CD000400.pub4 [PubMed 31535715]
  35. Brix AE. Renal papillary necrosis. Toxicol Pathol. 2002;30(6):672-674. doi:10.1080/01926230290166760 [PubMed 12512867]
  36. Brockow K, Przybilla B, Aberer W, et al. Guideline for the diagnosis of drug hypersensitivity reactions: S2K-Guideline of the German Society for Allergology and Clinical Immunology (DGAKI) and the German Dermatological Society (DDG) in collaboration with the Association of German Allergologists (AeDA), the German Society for Pediatric Allergology and Environmental Medicine (GPA), the German Contact Dermatitis Research Group (DKG), the Swiss Society for Allergy and Immunology (SGAI), the Austrian Society for Allergology and Immunology (ÖGAI), the German Academy of Allergology and Environmental Medicine (DAAU), the German Center for Documentation of Severe Skin Reactions and the German Federal Institute for Drugs and Medical Products (BfArM). Allergo J Int. 2015;24(3):94-105. doi:10.1007/s40629-015-0052-6 [PubMed 26120552]
  37. Brogden RN, Pinder RM, Sawyer PR, Speight TM, Avery GS. Naproxen: a review of its pharmacological properties and therapeutic efficacy and use. Drugs. 1975;9(5):326-363. [PubMed 1097233]
  38. Brooks PM, Day RO. Nonsteroidal Anti-inflammatory Drugs - Differences and Similarities. N Engl J Med. 1991;324(24):1716-1725. [PubMed 2034249]
  39. Brophy PD. Changing the paradigm in pediatric acute kidney injury. J Pediatr. 2013;162(6):1094-1096. doi:10.1016/j.jpeds.2013.01.065 [PubMed 23453549]
  40. Burch R. Epidemiology and treatment of menstrual migraine and migraine during pregnancy and lactation: a narrative review. Headache. 2020;60(1):200-216. doi:10.1111/head.13665 [PubMed 31579938]
  41. Capone ML, Sciulli MG, Tacconelli S, et al. Pharmacodynamic Interaction of Naproxen With Low-Dose Aspirin in Healthy Subjects. J Am Coll Cardiol. 2005, 45(8):1295-1301. [PubMed 15837265]
  42. Capone ML, Tacconelli S, Sciulli MG, et al. Clinical pharmacology of platelet, monocyte, and vascular cyclooxygenase inhibition by naproxen and low-dose aspirin in healthy subjects. Circulation. 2004;109(12):1468-1471. doi:10.1161/01.CIR.0000124715.27937.78 [PubMed 15037526]
  43. Catella-Lawson F, Reilly MP, Kapoor SC, et al. Cyclooxygenase Inhibitors and the Antiplatelet Effects of Aspirin. N Engl J Med. 2001; 345(25):1809-1817. [PubMed 11752357]
  44. Caughey GE, Cleland LG, Penglis PS, Gamble JR, James MJ. Roles of cyclooxygenase (COX)-1 and COX-2 in prostanoid production by human endothelial cells: selective up-regulation of prostacyclin synthesis by COX-2. J Immunol. 2001;167(5):2831-2838. doi:10.4049/jimmunol.167.5.2831 [PubMed 11509629]
  45. Chalasani NP, Maddur H, Russo MW, Wong RJ, Reddy KR; Practice Parameters Committee of the American College of Gastroenterology. ACG clinical guideline: diagnosis and management of idiosyncratic drug-induced liver injury. Am J Gastroenterol. 2021;116(5):878-898. doi:10.14309/ajg.0000000000001259 [PubMed 33929376]
  46. Chan AT, Manson JE, Albert CM, et al. Nonsteroidal antiinflammatory drugs, acetaminophen, and the risk of cardiovascular events. Circulation. 2006;113(12):1578-1587. doi:10.1161/CIRCULATIONAHA.105.595793 [PubMed 16534006]
  47. Chang RW, Tompkins DM, Cohn SM. Are NSAIDs safe? Assessing the risk-benefit profile of nonsteroidal anti-inflammatory drug use in postoperative pain management. Am Surg. 2021;87(6):872-879. doi:10.1177/0003134820952834 [PubMed 33238721]
  48. Cheng Y, Austin SC, Rocca B, et al. Role of prostacyclin in the cardiovascular response to thromboxane A2. Science. 2002;296(5567):539-541. doi:10.1126/science.1068711 [PubMed 11964481]
  49. Chong I, Chao A. Stevens-Johnson syndrome/toxic epidermal necrolysis and treatment with a biologic: a case report. Perm J. 2017;21:16-060. doi:10.7812/TPP/16-060 [PubMed 28488978]
  50. Chou R, Gordon DB, de Leon-Casasola OA, et al. Management of postoperative pain: a clinical practice guideline from the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists' Committee on Regional Anesthesia, Executive Committee, and Administrative Council [published correction appears in J Pain. 2016a;17(4):508-510]. J Pain. 2016;17(2):131-157. doi:10.1016/j.jpain.2015.12.008 [PubMed 26827847]
  51. Chou CI, Shih CJ, Chen YT, et al. Adverse effects of oral nonselective and cyclooxygenase-2-selective NSAIDs on hospitalization for acute kidney injury: a nested case-control cohort study. Medicine (Baltimore). 2016b;95(9):e2645. doi:10.1097/MD.0000000000002645 [PubMed 26945352]
  52. Clinch D, Banerjee AK, Ostick G. Absence of abdominal pain in elderly patients with peptic ulcer. Age Ageing. 1984;13(2):120-123. [PubMed 6731166]
  53. Clive DM, Stoff JS. Renal syndromes associated with nonsteroidal antiinflammatory drugs. N Engl J Med. 1984;310(9):563-572. doi:10.1056/NEJM198403013100905 [PubMed 6363936]
  54. Conlin P, Moore T, Swartz S, et al. Effect of Indomethacin on Blood Pressure Lowering by Captopril and Losartan in Hypertensive Patients. Hypertension. 2000;36(3):461-465. [PubMed 10988282]
  55. Cryer B, Feldman M. Cyclooxygenase-1 and cyclooxygenase-2 selectivity of widely used nonsteroidal anti-inflammatory drugs. Am J Med. 1998;104(5):413-421. doi:10.1016/s0002-9343(98)00091-6 [PubMed 9626023]
  56. Dathe K, Hultzsch S, Pritchard LW, Schaefer C. Risk estimation of fetal adverse effects after short-term second trimester exposure to non-steroidal anti-inflammatory drugs: a literature review. Eur J Clin Pharmacol. 2019;75(10):1347-1353. doi:10.1007/s00228-019-02712-2 [PubMed 31273431]
  57. Davidson BL, Verheijen S, Lensing AW, et al. Bleeding risk of patients with acute venous thromboembolism taking nonsteroidal anti-inflammatory drugs or aspirin. JAMA Intern Med. 2014;174(6):947-953. doi:10.1001/jamainternmed.2014.946 [PubMed 24733305]
  58. Davies NM, Anderson KE. Clinical pharmacokinetics of naproxen. Clin Pharmacokinet. 1997;32(4):268-293. doi:10.2165/00003088-199732040-00002 [PubMed 9113437]
  59. Delzer LM, Golightly LK, Kiser TH, Biggins SW, Lewis VJ, Kim II. Calcineurin inhibitor and nonsteroidal anti-inflammatory drug interaction: implications of changes in renal function associated with concurrent use. J Clin Pharmacol. 2018;58(11):1443-1451. doi:10.1002/jcph.1264 [PubMed 29799625]
  60. Demirag MD, Ozenirler S, Goker B, Poyraz A, Haznedaroglu S, Ozturk MA. Idiosyncratic toxic hepatitis secondary to single dose of naproxen. Acta Gastroenterol Belg. 2007;70(2):247-248. [PubMed 17715646]
  61. Derosier FJ, Lewis D, Hershey AD, et al. Randomized trial of sumatriptan and naproxen sodium combination in adolescent migraine. Pediatrics. 2012;129(6):e1411-1420. [PubMed 22585767]
  62. De Silva B, Banney L, Uttley W, Luqmani R, Schofield O. Pseudoporphyria and nonsteroidal antiinflammatory agents in children with juvenile idiopathic arthritis. Pediatr Dermatol. 2000;17(6):480-483. doi:10.1046/j.1525-1470.2000.01827.x [PubMed 11123786]
  63. Dionne R. Additive Analgesia Without Opioid Side Effects. Compend Contin Educ Dent. 2000;21(7):572-574, 576-577. [PubMed 11199661]
  64. Dionne RA, Berthold CW. Therapeutic Uses of Nonsteroidal Anti-inflammatory Drugs in Dentistry. Crit Rev Oral Biol Med. 2001;12(4):315-330. [PubMed 11603504]
  65. Doña I, Blanca-López N, Jagemann LR, et al. Response to a selective COX-2 inhibitor in patients with urticaria/angioedema induced by nonsteroidal anti-inflammatory drugs. Allergy. 2011;66(11):1428-1433. doi:10.1111/j.1398-9995.2011.02684.x [PubMed 21834936]
  66. Donati M, Conforti A, Lenti MC, et al. Risk of acute and serious liver injury associated to nimesulide and other NSAIDs: data from drug-induced liver injury case-control study in Italy. Br J Clin Pharmacol. 2016;82(1):238-248. doi:10.1111/bcp.12938 [PubMed 26991794]
  67. Drugs for Pain. Med Lett Drugs Ther. 2000;42(1085):73-78. [PubMed 10951654]
  68. EC-Naprosyn, Naprosyn, Anaprox DS (naproxen) tablets [prescribing information]. Alpharetta, GA: Canton Laboratories LLC; April 2021.
  69. Evers S, Afra J, Frese A, et al; European Federation of Neurological Societies. EFNS guideline on the drug treatment of migraine—revised report of an EFNS task force. Eur J Neurol. 2009;16(9):968-981. [PubMed 19708964]10.1111/j.1468-1331.2009.02748.x
  70. Ferraris VA, Saha SP, Oestreich JH, et al. 2012 Update to the Society of Thoracic Surgeons Guideline on Use of Antiplatelet Drugs in Patients Having Cardiac and Noncardiac Operations. Ann Thorac Surg. 2012;94(5):1761-1781. [PubMed 23098967]
  71. FitzGerald JD, Dalbeth N, Mikuls T, et al. 2020 American College of Rheumatology guideline for the management of gout. Arthritis Care Res (Hoboken). 2020;72(6):744-760. doi:10.1002/acr.24180 [PubMed 32391934]
  72. Forbes JA, Keller CK, Smith JW, et al. Analgesic Effect of Naproxen Sodium, Codeine, a Naproxen-Codeine Combination and Aspirin on the Postoperative Pain of Oral Surgery. Pharmacotherapy. 1986;6(5):211-218. [PubMed 3540871]
  73. Frank J, Poblete-Gutiérrez PA, Lang E. Porphyria. In: Bolognia JL, Schaffer JV, Cerroni L, eds. Dermatology. 4th ed. Elsevier; 2018:chap. 49 [PubMed Frank.2018]
  74. Fraser IS, McCarron G. Randomized trial of 2 hormonal and 2 prostaglandin-inhibiting agents in women with a complaint of menorrhagia. Aust N Z J Obstet Gynaecol. 1991;31(1):66-70. doi:10.1111/j.1479-828x.1991.tb02769.x [PubMed 1872778]
  75. Frontera JA, Lewin JJ 3rd, Rabinstein AA, et al. Guideline for reversal of antithrombotics in intracranial hemorrhage: a statement for healthcare professionals from the Neurocritical Care Society and Society of Critical Care Medicine. Neurocrit Care. 2016;24(1):6-46. [PubMed 26714677]
  76. Funder JW, Carey RM, Mantero F, et al. The management of primary aldosteronism: case detection, diagnosis, and treatment: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016;101(5):1889-1916. doi:10.1210/jc.2015-4061 [PubMed 26934393]
  77. Gaffo AL. Treatment of gout flares. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed January 20, 2022.
  78. Garratty G, Arndt PA. Drugs that have been shown to cause drug-induced immune hemolytic anemia or positive direct antiglobulin tests: some interesting findings since 2007. Immunohematology. 2014;30(2):66-79. [PubMed 25247621]
  79. Géraud G, Lantéri-Minet M, Lucas C, Valade D; French Society for the Study of Migraine Headache (SFEMC). French guidelines for the diagnosis and management of migraine in adults and children. Clin Ther. 2004;26(8):1305-1318. doi:10.1016/s0149-2918(04)80161-9 [PubMed 15476911]
  80. Gladding PA, Webster MW, Farrell HB, Zeng IS, Park R, Ruijne N. The antiplatelet effect of six non-steroidal anti-inflammatory drugs and their pharmacodynamic interaction with aspirin in healthy volunteers. Am J Cardiol. 2008;101(7):1060-1063. doi:10.1016/j.amjcard.2007.11.054 [PubMed 18359332]
  81. Goldenberg NA, Jacobson L, Manco-Johnson MJ. Brief communication: duration of platelet dysfunction after a 7-day course of Ibuprofen. Ann Intern Med. 2005;142(7):506-509. doi:10.7326/0003-4819-142-7-200504050-00009 [PubMed 15809462]
  82. Gooch K, Culleton BF, Manns BJ, et al. NSAID use and progression of chronic kidney disease. Am J Med. 2007;120(3):280.e1-280.e2807. doi:10.1016/j.amjmed.2006.02.015 [PubMed 17349452]
  83. Graham DJ, Campen D, Hui R, et al. Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case-control study. Lancet. 2005;365(9458):475-481. doi:10.1016/S0140-6736(05)17864-7 [PubMed 15705456]
  84. Graham DY. Prevention of Gastroduodenal Injury Induced by Chronic Nonsteroidal Anti-inflammatory Drug Therapy. Gastroenterology. 1989;96(2, pt 2)(suppl):675-681. [PubMed 2642452]
  85. Guerrero Gómez DA, París Zorro S, Aponte Barrios W, Carrillo Bayona JA. Drug reaction with eosinophilia and systemic symptoms (DRESS) with severe and atypical lung involvement. Radiol Case Rep. 2020;15(11):2178-2182. doi:10.1016/j.radcr.2020.08.037 [PubMed 32944113]
  86. Gulmez SE, Larrey D, Pageaux GP, et al. Transplantation for acute liver failure in patients exposed to NSAIDs or paracetamol (acetaminophen): the multinational case-population SALT study. Drug Saf. 2013;36(2):135-144. doi:10.1007/s40264-012-0013-7 [PubMed 23325533]
  87. Gulmez SE, Unal US, Lassalle R, Chartier A, Grolleau A, Moore N. Risk of hospital admission for liver injury in users of NSAIDs and nonoverdose paracetamol: Preliminary results from the EPIHAM study. Pharmacoepidemiol Drug Saf. 2018;27(11):1174-1181. doi:10.1002/pds.4640 [PubMed 30112779]
  88. Gunner KB, Smith HD, Ferguson LE. Practice guideline for diagnosis and management of migraine headaches in children and adolescents: Part two. J Pediatr Health Care. 2008;22(1):52-59. doi:10.1016/j.pedhc.2007.10.009 [PubMed 18174091]
  89. Gurwitz JH, Avorn J, Ross-Degnan D, et al. Nonsteroidal Anti-inflammatory Drug-Associated Azotemia in the Very Old. JAMA. 1990;264(4):471-475. [PubMed 2366280]
  90. Haag MD, Bos MJ, Hofman A, Koudstaal PJ, Breteler MM, Stricker BH. Cyclooxygenase selectivity of nonsteroidal anti-inflammatory drugs and risk of stroke. Arch Intern Med. 2008;168(11):1219-1224. doi:10.1001/archinte.168.11.1219 [PubMed 18541831]
  91. Hawkey CJ, Karrasch JA, Szczepañski L, et al. Omeprazole Compared With Misoprostol for Ulcers Associated With Nonsteroidal Anti-inflammatory Drugs. N Engl J Med. 1998;338(11):727-734. [PubMed 9494149]
  92. Heerdink ER, Leufkens HG, Herings RM, et al. NSAIDs Associated With Increased Risk of Congestive Heart Failure in Elderly Patients Taking Diuretics. Arch Intern Med. 1998;158(10):1108-1112. [PubMed 9605782]
  93. Hippisley-Cox J, Coupland C. Risk of myocardial infarction in patients taking cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs: population based nested case-control analysis. BMJ. 2005;330(7504):1366. doi:10.1136/bmj.330.7504.1366 [PubMed 15947398]
  94. Hollingworth P. The use of non-steroidal anti-inflammatory drugs in paediatric rheumatic diseases. Br J Rheumatol. 1993;32(1):73-77. [PubMed 8422565]
  95. Hong Y, Gengo FM, Rainka MM, Bates VE, Mager DE. Population pharmacodynamic modelling of aspirin- and Ibuprofen-induced inhibition of platelet aggregation in healthy subjects. Clin Pharmacokinet. 2008;47(2):129-137. doi:10.2165/00003088-200847020-00006 [PubMed 18193919]
  96. Hoppmann RA, Peden JG, Ober SK. Central Nervous System Side Effects of Nonsteroidal Anti-inflammatory Drugs. Aseptic Meningitis, Psychosis, and Cognitive Dysfunction. Arch Intern Med. 1991;151(7):1309-1313. [PubMed 2064481]
  97. Horsley RD, Vogels ED, McField DAP, et al. Multimodal postoperative pain control is effective and reduces opioid use after laparoscopic Roux-en-Y gastric bypass. Obes Surg. 2019;29(2):394-400. doi:10.1007/s11695-018-3526-z [PubMed 30317488]
  98. Howard AM, Dowling J, Varigos G. Pseudoporphyria due to naproxen. Lancet. 1985;1(8432):819-820. doi:10.1016/s0140-6736(85)91478-3 [PubMed 2858695]
  99. Huerta C, Castellsague J, Varas-Lorenzo C, García Rodríguez LA. Nonsteroidal anti-inflammatory drugs and risk of ARF in the general population. Am J Kidney Dis. 2005;45(3):531-539. doi:10.1053/j.ajkd.2004.12.005 [PubMed 15754275]
  100. Ito S. Drug therapy for breast-feeding women. N Engl J Med. 2000;343(2):118-126. [PubMed 10891521]
  101. Ito S, Blajchman A, Stephenson M, Eliopoulos C, Koren G. Prospective follow-up of adverse reactions in breast-fed infants exposed to maternal medication. Am J Obstet Gynecol. 1993;168(5):1393-1399. [PubMed 8498418]
  102. Jacobi J, Fraser GL, Coursin DB, et al. Clinical Practice Guidelines for the Sustained Use of Sedatives and Analgesics in the Critically Ill Adult. Crit Care Med. 2002;30(1):119-141. http://www.sccm.org/pdf/sedatives.pdf [PubMed 11902253]
  103. Jamali F, Stevens DR. Naproxen excretion in milk and its uptake by the infant. Drug Intell Clin Pharm. 1983;17(12):910-911. [PubMed 6653409]
  104. Jamali F, Tam YK, Stevens RD. Naproxen excretion in breast milk and its uptake by suckling infant. Drug Intell Clin Pharm. 1982;16(6):475.
  105. Janssens HJ, Janssen M, van de Lisdonk EH, van Riel PL, van Weel C. Use of oral prednisolone or naproxen for the treatment of gout arthritis: a double-blind, randomised equivalence trial. Lancet. 2008;371(9627):1854-1860. doi:10.1016/S0140-6736(08)60799-0 [PubMed 18514729]
  106. Kaunitz AM. Abnormal uterine bleeding in nonpregnant reproductive-age patients: management. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed November 29, 2022.
  107. Kean WF, Lock CJ, Rischke J, Butt R, Buchanan WW, Howard-Lock H. Effect of R and S enantiomers of naproxen on aggregation and thromboxane production in human platelets. J Pharm Sci. 1989;78(4):324-327. doi:10.1002/jps.2600780413 [PubMed 2724096]
  108. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 Clinical Practice Guidelines for the Evaluation and Management of Chronic Kidney Disease. Kidney Inter. 2013;3(suppl):1-150.
  109. Kim YJ, Lim KH, Kim MY, et al. Cross-reactivity to acetaminophen and celecoxib according to the type of nonsteroidal anti-inflammatory drug hypersensitivity. Allergy Asthma Immunol Res. 2014;6(2):156-162. doi:10.4168/aair.2014.6.2.156 [PubMed 24587953]
  110. Klar H, Sotošek N, Šelb J, Košnik M. Selective hypersensitivity to a single nonsteroidal anti-inflammatory drug. Acta Dermatovenerol Alp Pannonica Adriat. 2019;28(3):97-101. [PubMed 31545385]
  111. Klote MM, Smith LJ. A case of anaphylaxis to naproxen. Allergy. 2005;60(2):260-261. doi:10.1111/j.1398-9995.2004.00630.x [PubMed 15647052]
  112. Knodel LC. Preventing NSAID-Induced Ulcers: The Role of Misoprostol. Consult Pharm. 1989;4:37-41.
  113. Knowles SR, Drucker AM, Weber EA, Shear NH. Management options for patients with aspirin and nonsteroidal antiinflammatory drug sensitivity. Ann Pharmacother. 2007;41(7):1191-1200. doi:10.1345/aph.1K023 [PubMed 17609236]
  114. Kohli P, Steg PG, Cannon CP, et al. NSAID use and association with cardiovascular outcomes in outpatients with stable atherothrombotic disease. Am J Med. 2014;127(1):53-60.e1. doi:10.1016/j.amjmed.2013.08.017 [PubMed 24280110]
  115. Koncicki HM, Unruh M, Schell JO. Pain management in CKD: a guide for nephrology providers. Am J Kidney Dis. 2017;69(3):451-460. doi:10.1053/j.ajkd.2016.08.039 [PubMed 27881247]
  116. Kowalski ML, Makowska JS, Blanca M, et al. Hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs) - classification, diagnosis and management: review of the EAACI/ENDA(#) and GA2LEN/HANNA*. Allergy. 2011;66(7):818-829. doi:10.1111/j.1398-9995.2011.02557.x [PubMed 21631520]
  117. Kowalski ML, Asero R, Bavbek S, et al. Classification and practical approach to the diagnosis and management of hypersensitivity to nonsteroidal anti-inflammatory drugs. Allergy. 2013;68(10):1219-1232. doi:10.1111/all.12260 [PubMed 24117484]
  118. Kowalski ML, Makowska JS. Seven steps to the diagnosis of NSAIDs hypersensitivity: how to apply a new classification in real practice? Allergy Asthma Immunol Res. 2015;7(4):312-320. doi:10.4168/aair.2015.7.4.312 [PubMed 25749768]
  119. Kowalski ML, Agache I, Bavbek S, et al. Diagnosis and management of NSAID-Exacerbated Respiratory Disease (N-ERD)-a EAACI position paper. Allergy. 2019;74(1):28-39. doi:10.1111/all.13599 [PubMed 30216468]
  120. Kurella M, Bennett WM, Chertow GM. Analgesia in patients with ESRD: a review of available evidence. Am J Kidney Dis. 2003;42(2):217-228. doi:10.1016/s0272-6386(03)00645-0 [PubMed 12900801]
  121. Lago P, Bettiol T, Salvadori S, et al. Safety and efficacy of ibuprofen versus indomethacin in preterm infants treated for patent ductus arteriosus: a randomised controlled trial. Eur J Pediatr. 2002;161(4):202-207. doi:10.1007/s00431-002-0915-y [PubMed 12014386]
  122. Laidlaw TM, Cahill KN. Current knowledge and management of hypersensitivity to aspirin and NSAIDs. J Allergy Clin Immunol Pract. 2017;5(3):537-545. doi:10.1016/j.jaip.2016.10.021 [PubMed 28483309]
  123. Laine L, Curtis SP, Cryer B, Kaur A, Cannon CP. Risk factors for NSAID-associated upper GI clinical events in a long-term prospective study of 34 701 arthritis patients. Aliment Pharmacol Ther. 2010;32(10):1240-1248. doi:10.1111/j.1365-2036.2010.04465.x [PubMed 20955443]
  124. Lamberts M, Lip GY, Hansen ML, et al. Relation of nonsteroidal anti-inflammatory drugs to serious bleeding and thromboembolism risk in patients with atrial fibrillation receiving antithrombotic therapy: a nationwide cohort study. Ann Intern Med. 2014;161(10):690-698. doi:10.7326/M13-1581 [PubMed 25402512]
  125. Lang BA, Finlayson LA. Naproxen-Induced Pseudoporphyria in Patients With Juvenile Rheumatoid Arthritis. J Pediatr. 1994;124(4):639-642. [PubMed 8151484]
  126. Langman MJ, Weil J, Wainwright P, et al. Risks of bleeding peptic ulcer associated with individual non-steroidal anti-inflammatory drugs. Lancet. 1994;343(8905):1075-1078. doi:10.1016/s0140-6736(94)90185-6 [PubMed 7909103]
  127. Lapi F, Azoulay L, Yin H, Nessim SJ, Suissa S. Concurrent use of diuretics, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers with non-steroidal anti-inflammatory drugs and risk of acute kidney injury: nested case-control study. BMJ. 2013;346:e8525. doi:10.1136/bmj.e8525 [PubMed 23299844]
  128. Lethaby A, Wise MR, Weterings MA, Bofill Rodriguez M, Brown J. Combined hormonal contraceptives for heavy menstrual bleeding. Cochrane Database Syst Rev. 2019;2(2):CD000154. doi:10.1002/14651858.CD000154.pub3 [PubMed 30742315]
  129. Litalien C, Jacqz-Aigrain E. Risks and benefits of nonsteroidal anti-inflammatory drugs in children: a comparison with paracetamol. Paediatr Drugs. 2001;3(11):817-858. [PubMed 11735667]
  130. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Ibuprofen. Updated April 16, 2018. https://www.ncbi.nlm.nih.gov/books/NBK547845/. Accessed November 9, 2021.
  131. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Naproxen. Updated March 20, 2020. https://www.ncbi.nlm.nih.gov/books/NBK548159/?report=classic. Accessed November 9, 2021.
  132. Martin E, Vickers B, Landau R, Reece-Stremtan S. ABM clinical protocol #28, peripartum analgesia and anesthesia for the breastfeeding mother. Breastfeed Med. 2018;13(3):164-171. doi:10.1089/bfm.2018.29087.ejm [PubMed 29595994]
  133. Martinez R, Smith DW, Frankel LR. Severe Metabolic Acidosis After Acute Naproxen Sodium Ingestion. Ann Emerg Med. 1989;18(10):1102-1104. [PubMed 2552870]
  134. McDonald SA, Hershey AD, Pearlman E, et al. Long-term evaluation of sumatriptan and naproxen sodium for the acute treatment of migraine in adolescents. Headache. 2011;51(9):1374-1387. doi:10.1111/j.1526-4610.2011.01965.x [PubMed 21797863]
  135. McInerney KA, Hatch EE, Wesselink AK, Rothman KJ, Mikkelsen EM, Wise LA. Preconception use of pain-relievers and time-to-pregnancy: a prospective cohort study. Hum Reprod. 2017;32(1):103-111. doi:10.1093/humrep/dew272 [PubMed 27816920]
  136. Mechanick JI, Youdim A, Jones DB, et al. Clinical practice guidelines for the perioperative nutritional, metabolic, and nonsurgical support of the bariatric surgery patient--2013 update: cosponsored by American Association of Clinical Endocrinologists, the Obesity Society, and American Society for Metabolic & Bariatric Surgery. Surg Obes Relat Dis. 2013;9(2):159-191. doi:10.1016/j.soard.2012.12.010 [PubMed 23537696]
  137. Mérida E, Praga M. NSAIDs and nephrotic syndrome. Clin J Am Soc Nephrol. 2019;14(9):1280-1282. doi:10.2215/CJN.08090719 [PubMed 31416889]
  138. Misurac JM, Knoderer CA, Leiser JD, Nailescu C, Wilson AC, Andreoli SP. Nonsteroidal anti-inflammatory drugs are an important cause of acute kidney injury in children. J Pediatr. 2013;162(6):1153-1159.e1. doi:10.1016/j.jpeds.2012.11.069 [PubMed 23360563]
  139. Mohammed EP, Stevens JM. Recurrence of arthrotec-associated nephrotic syndrome with re-challenge. Clin Nephrol. 2000;53(6):483-485. [PubMed 10879670]
  140. Morgan TO, Anderson A, Bertram D. Effect of Indomethacin on Blood Pressure in Elderly People With Essential Hypertension Well Controlled on Amlodipine or Enalapril. Am J Hypertens. 2000;13(11):1161-1167. [PubMed 11078175]
  141. Nader DA, Schillaci RF. Pulmonary Infiltrates With Eosinophilia Due to Naproxen. Chest. 1983;83(2):280-282. [PubMed 6822116]
  142. Naprelan controlled release tablets (naproxen) [prescribing information]. Morristown, NJ: Almatica Pharma Inc; April 2021.
  143. Naprosyn (naproxen) [product monograph]: Brantford, Ontario, Canada: Methapharm Inc; January 2022.
  144. Naprosyn (naproxen) oral suspension [prescribing information]. Athens, GA: Athena Bioscience, LLC; April 2021.
  145. Naprosyn tablet (naproxen) [prescribing information]. Mississauga, Ontario: Hoffman-La Roche Limited; October 2014.
  146. Naproxen tablets [prescribing information]. East Windsor, NJ: Aurobindo Pharma; May 2021.
  147. Naproxen tablets [product monograph]. Laval, Quebec, Canada: Pro Doc Ltee; April 2022.
  148. Naproxen sodium tablets [prescribing information]. East Windsor, NJ: Aurobindo Pharma; May 2021.
  149. Nash DM, Markle-Reid M, Brimble KS, et al. Nonsteroidal anti-inflammatory drug use and risk of acute kidney injury and hyperkalemia in older adults: a population-based study. Nephrol Dial Transplant. 2019;34(7):1145-1154. doi:10.1093/ndt/gfz062 [PubMed 31264694]
  150. National Institute of Health and Care Excellence (NICE). Drug allergy: diagnosis and management. Clinical guideline 183. Published September 3, 2014. https://www.nice.org.uk/guidance/cg183. Accessed October 29, 2021. [PubMed 31264694]
  151. Nestvold K, Kloster R, Partinen M, Sulkava R. Treatment of acute migraine attack: naproxen and placebo compared. Cephalgia. 1985;5(2):115-119. [PubMed 3893730]
  152. Nguyen AM, Graham DY, Gage T, et al. Nonsteroidal Anti-inflammatory Drug Use in Dentistry: Gastrointestinal Implications. Gen Dent. 1999;47(6):590-596. [PubMed 10687453]
  153. Nissen SE, Yeomans ND, Solomon DH, et al. Cardiovascular safety of celecoxib, naproxen, or ibuprofen for arthritis. N Engl J Med. 2016;375(26):2519-2529. doi:10.1056/NEJMoa1611593 [PubMed 27959716]
  154. Oates JA, FitzGerald GA, Branch RA, Jackson EK, Knapp HR, Roberts LJ 2nd. Clinical implications of prostaglandin and thromboxane A2 formation (2). N Engl J Med. 1988;319(12):761-767. doi:10.1056/NEJM198809223191206 [PubMed 3045551]
  155. Ohlsson A, Walia R, Shah SS. Ibuprofen for the treatment of patent ductus arteriosus in preterm and/or low birth weight infants. Cochrane Database Syst Rev. 2013;(4):CD003481. doi:10.1002/14651858.CD003481.pub5 [PubMed 23633310]
  156. Onel KB, Horton DB, Lovell DJ, et al. 2021 American College of Rheumatology guideline for the treatment of juvenile idiopathic arthritis: recommendations for nonpharmacologic therapies, medication monitoring, immunizations, and imaging. Arthritis Care Res (Hoboken). 2022;74(4):505-520. doi:10.1002/acr.24839 [PubMed 35233989]
  157. Otani K, Tanigawa T, Watanabe T, et al. Microbiota plays a key role in non-steroidal anti-inflammatory drug-induced small intestinal damage. Digestion. 2017;95(1):22-28. doi:10.1159/000452356 [PubMed 28052268]
  158. Page J, Henry D. Consumption of NSAIDs and the Development of Congestive Heart Failure in Elderly Patients: An Underrecognized Public Health Problem. Arch Intern Med. 2000;160(6):777-784. [PubMed 10737277]
  159. Papatheodoridis GV, Sougioultzis S, Archimandritis AJ. Effects of Helicobacter pylori and nonsteroidal anti-inflammatory drugs on peptic ulcer disease: a systematic review. Clin Gastroenterol Hepatol. 2006;4(2):130-142. doi:10.1016/j.cgh.2005.10.006 [PubMed 16469671]
  160. Pediapharm Naproxen Suspension (naproxen) [product monograph]. Verdun, Quebec, Canada: Medexus Pharmaceuticals Inc; October 2021.
  161. Perez-Ruiz F. Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed October 22, 2020.
  162. Piper JM, Ray WA, Daugherty JR, Griffin MR. Corticosteroid use and peptic ulcer disease: role of nonsteroidal anti-inflammatory drugs. Ann Intern Med. 1991;114(9):735-740. doi:10.7326/0003-4819-114-9-735 [PubMed 2012355]
  163. pms-Naproxen (naproxen) [prescribing information]. Montreal, Quebec, Canada: Pharmascience Inc; June 2010.
  164. Pope JE, Anderson JJ, Felson DT. A Meta-analysis of the Effects of Nonsteroidal Anti-inflammatory Drugs on Blood Pressure. Arch Intern Med. 1993;153(4):477-484. [PubMed 8435027]
  165. Pounder R. Silent Peptic Ulceration: Deadly Silence or Golden Silence? Gastroenterology. 1989;96(2, pt 2)(suppl):626-631. [PubMed 2642448]
  166. Principles of Analgesic Use in the Treatment of Acute Pain and Cancer Pain. 6th ed. American Pain Society; 2008.
  167. Rahman S, Malcoun A. Nonsteroidal antiinflammatory drugs, cyclooxygenase-2, and the kidneys. Prim Care. 2014;41(4):803-821. doi:10.1016/j.pop.2014.09.001 [PubMed 25439535]
  168. Ray WA, Varas-Lorenzo C, Chung CP, et al. Cardiovascular risks of nonsteroidal antiinflammatory drugs in patients after hospitalization for serious coronary heart disease. Circ Cardiovasc Qual Outcomes. 2009;2(3):155-163. doi:10.1161/CIRCOUTCOMES.108.805689 [PubMed 20031832]
  169. Reece-Stremtan S, Campos M, Kokajko L; Academy of Breastfeeding Medicine. ABM clinical protocol #15: analgesia and anesthesia for the breastfeeding mother, revised 2017. Breastfeed Med. 2017;12(9):500-506. doi:10.1089/bfm.2017.29054.srt [PubMed 29624435]
  170. Richette P, Doherty M, Pascual E, et al. 2016 updated EULAR evidence-based recommendations for the management of gout. Ann Rheum Dis. 2017;76(1):29-42. doi:10.1136/annrheumdis-2016-209707 [PubMed 27457514]
  171. Ringold S, Angeles-Han ST, Beukelman T, et al. 2019 American College of Rheumatology/Arthritis Foundation guideline for the treatment of juvenile idiopathic arthritis: therapeutic approaches for non-systemic polyarthritis, sacroiliitis, and enthesitis. Arthritis Care Res (Hoboken). 2019;71(6):717-734. doi:10.1002/acr.23870 [PubMed 31021516]
  172. Roddy E, Clarkson K, Blagojevic-Bucknall M, et al. Open-label randomised pragmatic trial (CONTACT) comparing naproxen and low-dose colchicine for the treatment of gout flares in primary care. Ann Rheum Dis. 2020;79(2):276-284. doi:10.1136/annrheumdis-2019-216154 [PubMed 31666237]
  173. Runyon BA; AASLD. Introduction to the revised American Association for the Study of Liver Diseases practice guideline management of adult patients with ascites due to cirrhosis 2012. Hepatology. 2013;57(4):1651-1653. doi:10.1002/hep.26359 [PubMed 23463403]
  174. Ruperto N, Nikishina I, Pachanov ED, et al. A randomized, double-blind clinical trial of two doses of meloxicam compared with naproxen in children with juvenile idiopathic arthritis: short- and long-term efficacy and safety results. Arthritis Rheum. 2005;52(2):563-572. doi:10.1002/art.20860 [PubMed 15692986]
  175. Ruschitzka F, Borer JS, Krum H, et al. Differential blood pressure effects of ibuprofen, naproxen, and celecoxib in patients with arthritis: the PRECISION-ABPM (Prospective Randomized Evaluation of Celecoxib Integrated Safety Versus Ibuprofen or Naproxen Ambulatory Blood Pressure Measurement) Trial. Eur Heart J. 2017;38(44):3282-3292. doi:10.1093/eurheartj/ehx508 [PubMed 29020251]
  176. Rybo G, Nilsson S, Sikström B, Nygren KG. Naproxen in menorrhagia. Lancet. 1981;1(8220, pt 1):608-609. doi:10.1016/s0140-6736(81)92051-1 [PubMed 6110836]
  177. Sahu N, Roy J, Vunnam R, Golamari R, Jain R. Naproxen-induced thrombocytopenia. Proc (Bayl Univ Med Cent). 2020;33(4):653-654. doi:10.1080/08998280.2020.1798724 [PubMed 33100559]
  178. Sammaritano LR, Bermas BL, Chakravarty EE, et al. 2020 American College of Rheumatology guideline for the management of reproductive health in rheumatic and musculoskeletal diseases. Arthritis Rheumatol. 2020;72(4):529‐556. doi:10.1002/art.41191 [PubMed 32090480]
  179. Sanford-Driscoll M, Knodel LC. Induction of hemolytic anemia by nonsteroidal antiinflammatory drugs. Drug Intell Clin Pharm. 1986;20(12):925-934. doi:10.1177/106002808602001202 [PubMed 3545733]
  180. Sasi S, Altarawneh H, Petkar MA, Nair AP. Drug reaction with eosinophilia and systemic symptoms secondary to naproxen: a case report and literature review. Case Rep Acute Med. 2020;3:63–72. doi:10.1159/000509712
  181. Sawhney S, Woo P, Murray KJ. Macrophage activation syndrome: a potentially fatal complication of rheumatic disorders. Arch Dis Child. 2001;85(5):421-426. doi:10.1136/adc.85.5.421 [PubMed 11668110]
  182. Schjerning O, Larsen TB, Damkier P. The impact of selective and non-selective non-steroid anti-inflammatory drugs on secondary hemostasis in healthy volunteers. Thromb Res. 2009;124(2):208-212. doi:10.1016/j.thromres.2009.01.017 [PubMed 19269020]
  183. Schjerning Olsen AM, Fosbøl EL, Lindhardsen J, et al. Duration of treatment with nonsteroidal anti-inflammatory drugs and impact on risk of death and recurrent myocardial infarction in patients with prior myocardial infarction: a nationwide cohort study. Circulation. 2011;123(20):2226-2235. doi:10.1161/CIRCULATIONAHA.110.004671 [PubMed 21555710]
  184. Schjerning Olsen AM, Gislason GH, McGettigan P, et al. Association of NSAID use with risk of bleeding and cardiovascular events in patients receiving antithrombotic therapy after myocardial infarction. JAMA. 2015;313(8):805-814. doi:10.1001/jama.2015.0809 [PubMed 25710657]
  185. Schneider V, Lévesque LE, Zhang B, Hutchinson T, Brophy JM. Association of selective and conventional nonsteroidal antiinflammatory drugs with acute renal failure: A population-based, nested case-control analysis. Am J Epidemiol. 2006;164(9):881-889. doi:10.1093/aje/kwj331 [PubMed 17005625]
  186. Schwedt TJ, Garza Ivan. Acute treatment of migraine in adults. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed August 12, 2021.
  187. Schwenk ES. Nonopioid pharmacotherapy for acute pain in adults. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed December 11, 2020.
  188. Shah GM, Muhalwas KK, Winer RL. Renal papillary necrosis due to ibuprofen. Arthritis Rheum. 1981;24(9):1208-1210. doi:10.1002/art.1780240917 [PubMed 7306246]
  189. Shaunak S, Brown P, Morgan-Hughes JA. Exacerbation of Idiopathic Parkinson's Disease by Naproxen. BMJ, 1995;311(7002):422. [PubMed 7640588]
  190. Shi CL, Zhang Y, Zhang ZY, Zhou J, Tang XM. Comparative efficacy and safety of non-steroidal anti-inflammatory drugs in patients with juvenile idiopathic arthritis: a systematic review and network meta-analysis. Indian Pediatr. 2021;58(2):162-168. [PubMed 33632948]
  191. Silberstein SD. Practice parameter: evidence-based guidelines for migraine headache (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology [published correction appears in Neurology. 2000;56(1):142]. Neurology. 2000;55(6):754-762. [PubMed 10993991]
  192. Siu SS, Yeung JH, Lau TK. An in-vivo study on placental transfer of naproxen in early human pregnancy. Hum Reprod. 2002;17(4):1056-1059. doi:10.1093/humrep/17.4.1056 [PubMed 11925405]
  193. Sivera F, Andrés M, Carmona L, et al. Multinational Evidence-Based Recommendations for the Diagnosis and Management of Gout: Integrating Systematic Literature Review and Expert Opinion of a Broad Panel of Rheumatologists in the 3e Initiative. Ann Rheum Dis. 2014;73(2):328-335. [PubMed 23868909]
  194. Smith RP, Kaunitz AM. Dysmenorrhea in adult women: treatment. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed October 1, 2020.
  195. Snow V, Weiss K, Wall EM, et al. Pharmacologic Management of Acute Attacks of Migraine and Prevention of Migraine Headache. Ann Intern Med. 2002;137(10):840-849. [PubMed 12435222]
  196. Solomon DH. NSAIDs: therapeutic use and variability of response in adults. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed March 28, 2022.
  197. Solomon DH, Husni ME, Libby PA, et al. The risk of major NSAID toxicity with celecoxib, ibuprofen, or naproxen: a secondary analysis of the PRECISION trial. Am J Med. 2017;130(12):1415-1422.e4. doi:10.1016/j.amjmed.2017.06.028 [PubMed 28756267]
  198. Steinhubl SR. The Use of Anti-Inflammatory Analgesics in the Patient With Cardiovascular Disease: What a Pain. J Am Coll Cardiol. 2005.45(8):1302-1303. [PubMed 15837266]
  199. Stéphan JL, Koné-Paut I, Galambrun C, Mouy R, Bader-Meunier B, Prieur AM. Reactive haemophagocytic syndrome in children with inflammatory disorders. A retrospective study of 24 patients. Rheumatology (Oxford). 2001;40(11):1285-1292. doi:10.1093/rheumatology/40.11.1285 [PubMed 11709613]
  200. Strom BL, Carson JL, Schinnar R, Snyder ES, Shaw M, Lundin FE Jr. Nonsteroidal anti-inflammatory drugs and neutropenia. Arch Intern Med. 1993;153(18):2119-2124. [PubMed 8379803]
  201. Szeto CC, Sugano K, Wang JG, et al. Non-steroidal anti-inflammatory drug (NSAID) therapy in patients with hypertension, cardiovascular, renal or gastrointestinal comorbidities: joint APAGE/APLAR/APSDE/APSH/APSN/PoA recommendations. Gut. 2020;69(4):617-629. doi:10.1136/gutjnl-2019-319300 [PubMed 31937550]
  202. Thorell A, MacCormick AD, Awad S, et al. Guidelines for perioperative care in bariatric surgery: Enhanced Recovery After Surgery (ERAS) Society recommendations. World J Surg. 2016;40(9):2065-2083. doi:10.1007/s00268-016-3492-3 [PubMed 26943657]
  203. Trelle S, Reichenbach S, Wandel S, et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ. 2011;342:c7086. doi:10.1136/bmj.c7086 [PubMed 21224324]
  204. US Food and Drug Administration (FDA). FDA recommends avoiding use of NSAIDs in pregnancy at 20 weeks or later because they can result in low amniotic fluid. https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-avoiding-use-nsaids-pregnancy-20-weeks-or-later-because-they-can-result-low-amniotic. Published October 15, 2020. Accessed October 20, 2020.
  205. US Food and Drug Administration (FDA). FDA Drug Safety Communication: FDA strengthens warning that non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) can cause heart attacks or strokes. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-strengthens-warning-non-aspirin-nonsteroidal-anti-inflammatory. Published July 9, 2015. Accessed October 20, 2021.
  206. Vadivel N, Trikudanathan S, Singh AK. Analgesic nephropathy. Kidney Int. 2007;72(4):517-520. doi:10.1038/sj.ki.5002251 [PubMed 17410098]
  207. van Casteren DS, van den Brink AM, Terwindt GM. Migraine and other headache disorders in pregnancy. Handb Clin Neurol. 2020;172:187-199. doi:10.1016/B978-0-444-64240-0.00011-8 [PubMed 32768088]
  208. Van Overmeire B, Smets K, Lecoutere D, et al. A comparison of ibuprofen and indomethacin for closure of patent ductus arteriosus. N Engl J Med. 2000;343(10):674-681. doi:10.1056/NEJM200009073431001 [PubMed 10974130]
  209. Verbeeck RK. Pharmacokinetic Drug Interactions With Nonsteroidal Anti-inflammatory Drugs. Clin Pharmacokinet. 1990;19(1):44-66. [PubMed 2199127]
  210. Villanueva M, Heckenberger R, Palmér M, Schrör K. Stereospecific and non-stereospecific effects of ibuprofen on human platelet and polymorphonuclear leukocyte functions. Agents Actions Suppl. 1992;37:162-170. doi:10.1007/978-3-0348-7262-1_22 [PubMed 1321554]
  211. Wallace CA, Farrow D, Sherry DD. Increased risk of facial scars in children taking nonsteroidal antiinflammatory drugs. J Pediatr. 1994;125(5 Pt 1):819-822. doi:10.1016/s0022-3476(94)70084-2 [PubMed 7965441]
  212. Ward KE, Archambault R, Mersfelder TL. Severe adverse skin reactions to nonsteroidal antiinflammatory drugs: A review of the literature. Am J Health Syst Pharm. 2010;67(3):206-213. doi:10.2146/ajhp080603 [PubMed 20101062]
  213. Warner TD, Giuliano F, Vojnovic I, Bukasa A, Mitchell JA, Vane JR. Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis. Proc Natl Acad Sci U S A. 1999;96(13):7563-7568. doi:10.1073/pnas.96.13.7563 [PubMed 10377455]
  214. Watson DJ, Rhodes T, Cai B, Guess HA. Lower risk of thromboembolic cardiovascular events with naproxen among patients with rheumatoid arthritis. Arch Intern Med. 2002;162(10):1105-1110. doi:10.1001/archinte.162.10.1105 [PubMed 12020179]
  215. Weiss PF. Oligoarticular juvenile idiopathic arthritis. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com. Accessed April 22, 2022.
  216. Wesselink AK, Bresnick KA, Hatch EE, et al. Association between male use of pain medication and fecundability. Am J Epidemiol. 2020;189(11):1348-1359. doi:10.1093/aje/kwaa096 [PubMed 32488260]
  217. Whelton A, Stout RL, Spilman PS, Klassen DK. Renal effects of ibuprofen, piroxicam, and sulindac in patients with asymptomatic renal failure. A prospective, randomized, crossover comparison. Ann Intern Med. 1990;112(8):568-576. doi:10.7326/0003-4819-112-8-568 [PubMed 2183665]
  218. Whelton A. Nephrotoxicity of nonsteroidal anti-inflammatory drugs: physiologic foundations and clinical implications. Am J Med. 1999;106(5B):13S-24S. doi:10.1016/s0002-9343(99)00113-8 [PubMed 10390124]
  219. White AA, Stevenson DD. Aspirin-exacerbated respiratory disease. N Engl J Med. 2018;379(11):1060-1070. doi:10.1056/NEJMra1712125 [PubMed 30207919]
  220. Winner P, Linder S, Hershey AD. Consistency of response to sumatriptan/naproxen sodium in a randomized placebo-controlled, cross-over study for the acute treatment of migraine in adolescence. Headache. 2015;55(4):519-528. [PubMed 25881677]
  221. Worthington I, Pringsheim T, Gawel MJ, et al; Canadian Headache Society Acute Migraine Treatment Guideline Development Group. Canadian Headache Society guideline: acute drug therapy for migraine headache. Can J Neurol Sci. 2013;40(5)(suppl 3):S1-S80. [PubMed 23968886]
  222. Yancy CW, Jessup M, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2013;128(16):e240-e327. doi:10.1161/CIR.0b013e31829e8776 [PubMed 23741058]
  223. Yeomans ND, Graham DY, Husni ME, et al. Randomised clinical trial: gastrointestinal events in arthritis patients treated with celecoxib, ibuprofen or naproxen in the PRECISION trial. Aliment Pharmacol Ther. 2018;47(11):1453-1463. doi:10.1111/apt.14610 [PubMed 29667211]
  224. Yeomans ND, Tulassay Z, Juhasz L, et al. A Comparison of Omeprazole With Ranitidine for Ulcers Associated With Nonsteroidal Anti-inflammatory Drugs. N Engl J Med. 1998;338(11):719-726. [PubMed 9494148]
  225. Ylikorkala O, Pekonen F. Naproxen reduces idiopathic but not fibromyoma-induced menorrhagia. Obstet Gynecol. 1986;68(1):10-12. [PubMed 3523328]
  226. Zeltzer LK, Krane EJ, Levy RL. Pediatric pain management. In: Kliegman RM, St. Geme J, eds. Nelson Textbook of Pediatrics. 21st ed. Elsevier; 2020:chap. 76.
  227. Zhan M, Doerfler RM, Xie D, et al. Association of opioids and nonsteroidal anti-inflammatory drugs with outcomes in CKD: findings from the CRIC (Chronic Renal Insufficiency Cohort) Study. Am J Kidney Dis. 2020;76(2):184-193. doi:10.1053/j.ajkd.2019.12.010 [PubMed 32317121]
  228. Zhang W, Doherty M, Bardin T, et al. EULAR Evidence Based Recommendations for Gout. Part II: Management. Report of a Task Force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis. 2006;65(10):1312-1324. [PubMed 16707532]
  229. Zipser RD, Hoefs JC, Speckart PF, Zia PK, Horton R. Prostaglandins: modulators of renal function and pressor resistance in chronic liver disease. J Clin Endocrinol Metab. 1979;48(6):895-900. doi:10.1210/jcem-48-6-895 [PubMed 447795]
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