Health Canada has completed a safety review confirming that the use of nonsteroidal anti-inflammatory drugs (NSAIDs) starting from approximately 20 weeks of pregnancy or later may cause rare but serious kidney problems in an unborn baby. This can lead to low levels of amniotic fluid and possible complications, such as impaired lung maturation and limb contractures in the newborn baby. Health Canada is advising that pregnant women not use NSAIDs from approximately 20 to 28 weeks of pregnancy unless advised to do so by their health care provider. If a health care provider decides the use of NSAIDs between 20 and 28 weeks of pregnancy is necessary, Health Canada recommends that they use the lowest effective dose for the shortest duration possible and consider monitoring amniotic fluid levels via ultrasound if treatment extends beyond 48 hours. The use of NSAIDs remains contraindicated in the last trimester of pregnancy. The recommendations do not apply to the use of low-dose (81 mg) aspirin, pediatric-only formulations (those indicated only for children younger than 12 years), or ophthalmic formulations. Prescription and nonprescription NSAID product labels will be updated with this new information.
Further information is available at https://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2021/75763a-eng.php.
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.
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
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]).
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 (Gladman 2020).
Dysmenorrhea:
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 (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 (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 (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 (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 (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 (Mariano 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.
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).
There are no specific dosage adjustments provided in the manufacturer’s labeling; use with caution and consider using a reduced dose.
(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 the immediate release preparations.
Analgesia/pain, mild to moderate:
Children and Adolescents <60 kg: Limited data available: Oral: 5 to 6 mg/kg/dose every 12 hours; maximum daily dose: 1,000 mg/day (Berde 2002); doses as high as 10 mg/kg/dose have also been recommended (APS 2008)
Children and Adolescents ≥60 kg: Limited data available: Oral: 250 to 375 mg twice daily; maximum daily dose: 1,000 mg/day (Berde 2002)
OTC labeling: Children ≥12 years and Adolescents: Oral: 200 mg every 8 to 12 hours; if needed may take 400 mg for the initial dose; maximum daily dose: 600 mg/day
Fever: OTC labeling: Children ≥12 years and Adolescents: Oral: 200 mg every 8 to 12 hours; if needed may take 400 mg for the initial dose; maximum daily dose: 600 mg/day
Juvenile idiopathic arthritis: Children and Adolescents: Oral: 10 to 15 mg/kg/day in 2 divided doses; Maximum daily dose: 1,000 mg/day (Hollingsworth 1993; Kliegman 2016; Litalien 2001)
Ankylosing spondylitis: Limited data available: Children and Adolescents: Oral: 15 to 20 mg/kg/day in 2 divided doses; maximum daily dose: 1,500 mg/day; adult dosing suggests limiting this maximum daily dose to <6 months of therapy (APS 2008; Kliegman 2016)
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Manufacturer’s labeling: Children ≥2 years and Adolescents:
CrCl ≥30 mL/minute: There are no specific dosage adjustments provided in the manufacturer’s labeling; use with caution and consider using a reduced dose. Use is not recommended in patients with moderate renal impairment.
CrCl <30 mL/minute: Use is not recommended; avoid use in patients with advanced renal disease.
KDIGO 2012 guidelines provide the following recommendations for NSAIDs (KDIGO 2013): Children and Adolescents:
eGFR 30 to <60 mL/minute/1.73 m2: Temporarily discontinue in patients with intercurrent disease that increases risk of acute kidney injury
eGFR <30 mL/minute/1.73 m2: Avoid use
There are no specific dosage adjustments provided in the manufacturer’s labeling; use with caution and consider using a reduced dose.
Use with caution; consider using a reduced dose. Refer to adult dosing.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Capsule, Oral, as sodium:
Aleve: 220 mg [contains brilliant blue fcf (fd&c blue #1)]
Generic: 220 mg
Kit, Combination:
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 aluminum lake]
All Day Pain Relief: 220 mg [contains fd&c blue #2 aluminum lake]
All Day Relief: 220 mg [gluten free; contains fd&c blue #2 aluminum lake]
Anaprox DS: 550 mg [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 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
May be product dependent
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
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 aluminum lake]
Anaprox DS: 550 mg [contains fd&c blue #2 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)]
Generic: 750 mg
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Anaprox DS, EC-Naprosyn, Naprosyn tablets: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/017581s115,018164s065,020067s024lbl.pdf#page=23
Naprelan: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/020353s038lbl.pdf#page=23
Naprosyn suspension: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/018965s027lbl.pdf#page=23
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, cyclooxygenase-2 selective therapy (celecoxib 100 to 200 mg up to twice a day) should be used. 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.
Oral: Administer with food, milk, or antacids to decrease GI adverse effects. Shake suspension well before use. Do not chew, crush, or break delayed or controlled release tablet, swallow whole. Separate administration of naproxen and antacids, sucralfate, or cholestyramine by 2 hours.
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: 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.
Migraine, acute treatment
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
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]).
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]
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, NSAIDs may inhibit sodium resorption in the thick ascending loop of Henle and collecting tubule thereby causing sodium and fluid retention; as a result, NSAID use may result in hypertension and decreased efficacy of diuretics (Ref).
Onset: Variable; 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)
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)
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)
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) 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)
Use of nonsteroidal anti-inflammatory drugs (NSAIDs), including naproxen, is associated with an increased risk of several kidney-specific effects: acute kidney injury, interstitial nephritis (with or without nephrotic syndrome), and renal papillary necrosis.
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); persistent kidney function abnormalities may suggest additional etiology that may or may not be related to NSAID use.
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; these patients generally do not present with symptoms consistent with allergic AIN (eg, fever, rash, eosinophilia, eosinophiluria) that is often seen 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:
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)
• Nephrotic syndrome
• Volume depletion (eg, due to concomitant diuretic use, nausea, or vomiting)
• ≥65 years of age (Ref)
- Note: NSAID-associated AKI may also occur in pediatric patients, even at therapeutic doses (Ref)
• Heart failure (Ref)
• Cirrhosis (Ref)
• Concomitant use of diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or calcineurin inhibitors (Ref)
• Preexisting conditions which result in decreased renal blood flow or decreased effective arterial circulation (Ref)
• Preexisting conditions where renal blood flow/renal perfusion is dependent on prostaglandin-mediated vasodilation (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)
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)
Hepatic: Hepatotoxicity (idiosyncratic) (Chalasani 2021)
Immunologic: Drug reaction with eosinophilia and systemic symptoms (Guerrero Gómez 2020)
Renal: Acute kidney injury (Rahman 2014)
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).
Concerns related to adverse effects:
• Anaphylactoid reactions: Even in patients without prior exposure anaphylactoid reactions may occur; patients with "aspirin triad" (bronchial asthma, aspirin intolerance, rhinitis) may be at increased risk. Contraindicated in patients who experience bronchospasm, asthma, rhinitis, or urticaria with nonsteroidal anti-inflammatory drug (NSAID) or aspirin therapy.
• Cardiovascular events: [US Boxed Warning]: NSAIDs cause an increased risk of serious (and potentially fatal) adverse cardiovascular thrombotic events, including MI and stroke. Risk may occur early during treatment and may increase with duration of use. Relative risk appears to be similar in those with and without known cardiovascular disease or risk factors for cardiovascular disease; however, absolute incidence of serious cardiovascular thrombotic events (which may occur early during treatment) was higher in patients with known cardiovascular disease or risk factors and in those receiving higher doses. New-onset hypertension or exacerbation of hypertension may occur (NSAIDs may also impair response to ACE inhibitors, thiazide diuretics, or loop diuretics); may contribute to cardiovascular events; monitor blood pressure; use with caution in patients with hypertension. May cause sodium and fluid retention, use with caution in patients with edema. Avoid use in heart failure (ACCF/AHA [Yancy 2013]). Avoid use in patients with a recent MI unless benefits outweigh risk of cardiovascular thrombotic events. Use the lowest effective dose for the shortest duration of time, consistent with individual patient goals, to reduce risk of cardiovascular events; alternate therapies should be considered for patients at high risk.
• CNS effects: May cause drowsiness, dizziness, blurred vision, and other neurologic effects 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.
• Drug reaction with eosinophilia and systemic symptoms: Potentially serious, sometimes fatal, drug reaction with eosinophilia and systemic symptoms (DRESS), also known as multiorgan hypersensitivity reactions, has been reported with NSAIDs. Monitor for signs and symptoms (eg, fever, rash, lymphadenopathy, eosinophilia) in association with other organ system involvement (eg, hepatitis, nephritis, hematological abnormalities, myocarditis, myositis). Early symptoms of hypersensitivity reaction (eg, lymphadenopathy, fever) may occur without rash; discontinue therapy and further evaluate if DRESS is suspected.
• Gastrointestinal events: [US Boxed Warning]: NSAIDs cause increased risk of serious GI inflammation, ulceration, bleeding, and perforation (may be fatal); elderly patients and patients with history of peptic ulcer disease and/or GI bleeding are at greater risk of serious GI events. These events may occur at any time during therapy and without warning. Avoid use in patients with active GI bleeding. Use caution with a history of GI ulcers, concurrent therapy known to increase the risk of GI bleeding (eg, aspirin, anticoagulants and/or corticosteroids, selective serotonin reuptake inhibitors), advanced hepatic disease, coagulopathy, smoking, use of alcohol, or in elderly or debilitated patients. Use the lowest effective dose for the shortest duration of time, consistent with individual patient goals, to reduce risk of GI adverse events; alternate therapies should be considered for patients at high risk. When used concomitantly with aspirin, a substantial increase in the risk of GI complications (eg, ulcer) occurs; concomitant gastroprotective therapy (eg, proton pump inhibitors) is recommended (Bhatt 2008b).
• Hematologic effects: Platelet adhesion and aggregation may be decreased; may prolong bleeding time; patients with coagulation disorders or who are receiving anticoagulants should be monitored closely. Anemia may occur; patients on long-term NSAID therapy should be monitored for anemia. Rarely, NSAID use has been associated with potentially severe blood dyscrasias (eg, agranulocytosis, thrombocytopenia, aplastic anemia).
• Hepatic effects: Transaminase elevations have been reported with use; closely monitor patients with any abnormal LFT. Rare (sometimes fatal) severe hepatic reactions (eg, fulminant hepatitis, hepatic necrosis, hepatic failure) have occurred with NSAID use; discontinue immediately if signs or symptoms of hepatic disease develop or if systemic manifestations occur.
• Hyperkalemia: NSAID use may increase the risk of hyperkalemia, particularly in 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.
• Renal effects: NSAID use may compromise existing renal function; dose-dependent decreases in prostaglandin synthesis may result from NSAID use, reducing renal blood flow, which may cause renal decompensation (usually reversible). Patients with impaired renal function, dehydration, hypovolemia, heart failure, hepatic impairment, those taking diuretics and ACE inhibitors, and patients ≥65 years of age are at greater risk of renal toxicity. Rehydrate patient before starting therapy; monitor renal function closely. Long-term NSAID use may result in renal papillary necrosis and other renal injury.
• Skin reactions: NSAIDs may cause potentially fatal serious skin adverse events including exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN); may occur without warning; discontinue use at first sign of skin rash (or any other hypersensitivity).
Disease-related concerns:
• Aseptic meningitis: May increase the risk of aseptic meningitis, especially in patients with systemic lupus erythematosus (SLE) and mixed connective tissue disorders.
• Asthma: Contraindicated in patients with aspirin-sensitive asthma; severe and potentially fatal bronchospasm may occur. Use caution in patients with other forms of asthma.
• Bariatric surgery: Gastric ulceration: Avoid chronic use of oral nonselective NSAIDs after bariatric surgery; development of anastomotic ulcerations/perforations may occur (Bhangu 2014; Mechanick 2013). Short-term use of celecoxib or IV ketorolac are recommended as part of a multimodal pain management strategy for postoperative pain (Chou 2016a; Horsley 2019; Thorell 2016).
• Coronary artery bypass graft surgery: [US Boxed Warning]: Use is contraindicated in the setting of coronary artery bypass graft (CABG) surgery. Risk of MI and stroke may be increased with use following CABG surgery.
• Hepatic impairment: Use with caution in patients with hepatic impairment; patients with advanced hepatic disease are at an increased risk of GI bleeding with NSAIDs.
• Renal impairment: Avoid use in patients with advanced renal disease; discontinue use with persistent or worsening abnormal renal function tests.
Special populations:
• Elderly: Patients ≥65 years of age are at greater risk for serious GI, cardiovascular, and/or renal adverse events; use with caution.
• Pediatric: Not for self-medication (OTC use) in children <12 years.
Other warnings/precautions:
• Self-medication (OTC use): Prior to self-medication, patients should contact healthcare provider if they have had recurring stomach pain or upset, ulcers, bleeding problems, asthma, high BP, heart or kidney disease, other serious medical problems, are currently taking a diuretic, anticoagulant, other NSAIDs, or are ≥60 years of age. Recommended dosages and duration should not be exceeded, due to an increased risk of GI bleeding, MI, and stroke. Patients should stop use and consult a healthcare provider if symptoms get worse, newly appear, or continue; if an allergic reaction occurs; if feeling faint, vomit blood or have bloody/black stools; if having difficulty swallowing or heartburn, or if fever lasts for >3 days or pain >10 days. Consuming ≥3 alcoholic beverages/day or taking longer than recommended may increase the risk of GI bleeding.
• Surgical/dental procedures: Withhold for at least 4 to 6 half-lives prior to surgical or dental procedures.
Pseudoporphyria (ie, increased skin fragility and blistering with scarring in sun-exposed skin) has been reported in naproxen-treated children with JIA (reported incidence, 12%); discontinue therapy if this occurs (Lang 1994).
Substrate of CYP1A2 (minor), CYP2C9 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
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
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. Management: Consider avoiding this combination by temporarily suspending treatment with NSAIDs, or seeking alternatives to oral sodium phosphate bowel preparation. If the combination cannot be avoided, maintain adequate hydration and monitor renal function closely. Risk D: Consider therapy modification
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 (Tertiary Amine): May enhance the adverse/toxic effect of Nonsteroidal Anti-Inflammatory Agents (Nonselective). Specifically, the risk of major adverse cardiovascular events may be increased. Tricyclic Antidepressants (Tertiary Amine) may enhance the antiplatelet effect of Nonsteroidal Anti-Inflammatory Agents (Nonselective). 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
Naproxen absorption rate/levels may be decreased if taken with food. Management: Administer with food, milk, or antacids to decrease GI adverse effects.
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]).
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).
Maternal use of NSAIDs should be avoided 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 use should be avoided 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).
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 long-term use (>1 week) should be avoided 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, use of naproxen should be avoided 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. Maternal use of NSAIDs should be avoided if the breastfeeding infant has platelet dysfunction, thrombocytopenia, or a ductal-dependent cardiac lesion (ABM [Martin 2018]; ABM [Reece-Stremtan 2017]; Bloor 2013).
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.
CBC (if hemoglobin ≤10 g at initiation, continue to monitor hemoglobin periodically during long-term therapy), chemistry profile (periodically during long-term therapy), liver function tests, renal function tests (urine output, serum BUN and creatinine), blood pressure (at initiation and during therapy), signs/symptoms of fluid retention, periodic ophthalmic exam (with any vision changes occurring during long-term therapy), signs of bleeding (occult or gross blood loss).
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.
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%)
Renal function impairment: Metabolites and conjugates may accumulate.
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 - $2.53
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
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
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