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Mechanism of Action
US Drug Names
250 or 500 mg PO twice daily. May adjust the dose based on clinical response. Max: 1,500 mg/day for limited periods of up to 6 months. 
275 or 550 mg PO twice daily. May adjust the dose based on clinical response. Max: 1,500 mg/day for limited periods of up to 6 months.
375 or 500 mg PO twice daily. May adjust the dose based on clinical response. Max: 1,500 mg/day for limited periods of up to 6 months.
750 or 1,000 mg PO once daily. May adjust the dose based on clinical response. Max: 1,500 mg/day for limited periods.
5 mg/kg/dose (Max: 500 mg/dose) PO twice daily.
5 mg/kg/dose (Max: 500 mg/dose) PO twice daily.
NOTE: Delayed-release naproxen is not recommended for the treatment of acute gout because of the absorption delay as compared to other naproxen formulations.
750 mg PO once, then 250 mg PO every 8 hours as needed until the attack has subsided.  
825 mg PO once, then 275 mg PO every 8 hours as needed until the attack has subsided.
1,000 to 1,500 mg PO once, then 1,000 mg PO once daily as needed until the attack has subsided.
NOTE: Delayed-release naproxen is not recommended for the initial treatment of pain because the absorption is delayed as compared to other naproxen formulations.
NOTE: Naproxen sodium may be preferred to naproxen when fast-onset pain relief is needed.
500 mg PO once, then 250 mg PO every 6 to 8 hours as needed. Max: 1,250 mg/day. 
550 mg PO once, then 550 mg PO every 12 hours or 275 mg PO every 6 to 8 hours as needed. Max: 1,375 mg on day 1, then 1,100 mg/day.
1,000 or 1,500 mg PO once daily. Usual Max: 1,000 mg/day.
440 mg PO once, then 220 mg PO every 8 to 12 hours. Max: 660 mg/day.
440 mg PO once, then 220 mg PO every 8 to 12 hours. Max: 660 mg/day. Discontinue use if pain gets worse or lasts for more than 10 days.
440 mg PO once, then 220 mg PO every 8 to 12 hours. Max: 660 mg/day. Discontinue use if fever gets worse or lasts for more than 3 days.
500 mg PO as a single dose. Guidelines classify naproxen as having established efficacy for the treatment of acute migraine. 
550 mg PO as a single dose. Guidelines classify naproxen as having established efficacy for the treatment of acute migraine. 
500 or 550 mg PO once or twice daily for 6 days starting 2 to 7 days before the expected onset of menses and repeated monthly with each menstrual cycle.
250 mg PO 3 times daily for 6 weeks or 500 mg PO twice daily for 7 days after total hip arthroplasty. 
NOTE: Dosage expressed as naproxen base (200 mg naproxen base is equivalent to 220 mg naproxen sodium).
250 to 500 mg PO every 12 hours, initially; may increase dose up to 1,500 mg/day if tolerated and needed and continue for 1 to 2 weeks, then decrease dose by 125 to 250 mg/day every 1 to 2 weeks in combination with colchicine.
5 mg/kg/dose PO every 12 hours for 1 to 4 weeks; up to 15 mg/kg/day has been tolerated. Consider tapering dose gradually every 1 to 2 weeks. 
250 to 500 mg PO every 12 hours, initially; may increase dose up to 1,500 mg/day if tolerated and needed and continue for at least 2 to 4 weeks, then decrease dose by 125 to 250 mg/day every 1 to 2 weeks in combination with colchicine.
5 mg/kg/dose PO every 12 hours for at least 2 to 4 weeks in combination with colchicine; up to 15 mg/kg/day has been tolerated. Consider tapering dose gradually every 1 to 2 weeks. 
Naproxen 1500 mg/day PO; Naproxen sodium up to 1650 mg/day PO for limited periods. For non-prescription use: 660 mg/day PO.
>= 12 years: In clinical practice, 20 mg/kg/day PO not to exceed 1000 mg/day PO; for non-prescription use, 660 mg/day PO.
2 to < 12 years: In clinical practice, 20 mg/kg/day PO not to exceed 1000 mg/day PO; non-prescription (self medication) use is not recommended.
< 2 years: Safety and efficacy have not been established.
Safety and efficacy have not been established.
Although specific guidelines are not available, dosage reduction may be necessary in patients with hepatic dysfunction.
CrCl >= 30 ml/min: No dosage adjustment needed.
CrCl < 30 ml/min: Not recommended.
Naproxen is a nonsteroidal anti-inflammatory drug (NSAID) of the propionic acid chemical class. This medicine possesses antipyretic and analgesic properties. Naproxen is a propionic acid derivative related to ibuprofen, ketoprofen, flurbiprofen, and fenoprofen. Many pharmacodynamic similarities exist among these agents, which are usually better tolerated than aspirin or indomethacin. All NSAIDs, including naproxen, carry an increased risk of serious gastrointestinal adverse effects including bleeding, ulceration, and perforation of the stomach or intestines, and may cause an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke. The FDA approved labeling of both the OTC and prescription products stress dosing at the lowest effective dose for the shortest possible duration, as the risk for adverse effects may increase with increased use. A retrospective review by FDA Advisory Committees of short-term efficacy trials of non-prescription strength naproxen indicated that an increase in CV events was not apparent during the studies. However, it is important to note that CV risk was not the focus of the studies, and further information is needed to determine if a cause and effect relationship exists between non-prescription strength NSAID use and adverse cardiovascular outcomes. Naproxen is available as the anion and as the sodium salt; all formulations liberate naproxen as the active drug. Naproxen has been shown superior to ergotamine in the treatment of migraine. Naproxen was approved by the FDA in 1976. In January 1994, the FDA granted permission to market naproxen in a nonprescription form (e.g., Aleve).
The most frequently reported reactions to naproxen are gastrointestinal (GI) adverse events and may be more frequent with higher doses. NSAIDs cause an increased risk of serious gastrointestinal adverse events including inflammation, GI bleeding, ulceration (peptic ulcer), and GI perforation (gastric or intestinal). These events can be fatal and can occur at any time during therapy. Upper GI ulcers, bleeding, or perforation occur in approximately 1% of patients treated for 3 to 6 months, and in about 2% to 4% of patients treated for a year, with trends continuing with longer duration of use. Constipation, pyrosis (heartburn), abdominal pain, and nausea occur in 3% to 9% of patients. Dyspepsia was reported in less than 3% to 14% of patients. Diarrhea has occurred in less than 3% to 9% of patients. Flatulence, gastritis, vomiting, dysphagia, and stomatitis are reported less frequently (less than 3%). Gastrointestinal adverse events noted in less than 1% of patients during naproxen trials include GI bleeding, anorexia, cholecystitis, cholelithiasis, eructation, GI hemorrhage, rectal hemorrhage, aphthous stomatitis, ulcerative stomatitis, oral ulceration, peptic ulcer, periodontal abscess, cardiospasm, colitis, gastroenteritis, GI disorder, rectal disorder, tooth disorder, melena, esophagus ulcer, necrosis, and non-peptic GI ulcer. In patients taking NSAIDs in general, flatulence, GI bleeding, GI perforation, GI ulcers (gastric, duodenal), and vomiting were reported in 1% to 10%, while xerostomia and glossitis were reported in less than 1%. GI events noted in postmarketing reports include GI perforation, hematemesis, colitis, exacerbation of inflammatory bowel disease (ulcerative colitis, Crohn's disease), non-peptic GI ulceration, ulcerative stomatitis, and peptic ulcer. Adverse effects reported by patients with rheumatoid arthritis appear to be more severe and frequent with higher dosages (1.5 g/day) than with lower dosages (750 mg/day). Gastrointestinal bleeding or erosive gastritis can be minor or life-threatening and may result from a combination of direct irritant action on the stomach mucosa and a prolonged bleeding time, due to changes in platelet aggregation. Weight loss has been reported in less than 1% of patients during naproxen clinical trials. Weight changes and appetite changes have occurred in less than 1% of patients taking NSAIDs. The incidence of gastrointestinal events in pediatric trials was similar to adult trials. 
Esophagitis (< 1%) and esophageal ulceration (< 1%) have been reported in patients receiving NSAIDs, such as naproxen.  NSAID-induced esophagitis is characterized by sudden onset odynophagia, pyrosis (heartburn), retrosternal pain, and dysphagia. Severe complications such as esophageal ulceration, esophageal stricture, bleeding, and perforation have been reported rarely. Risk factors for NSAID-induced esophageal effects include taking the medication without water and at night. Symptoms usually resolve within days to weeks after stopping the medication.
Naproxen has been shown to cause platelet dysfunction; this effect, however, is transient and reversible. As inhibition of platelet aggregation appears to correlate with effective plasma concentrations of the drug, the individual half-life of each NSAID determines the duration of this effect. Naproxen glucuronide, a metabolite of naproxen, may cause immune-mediated thrombocytopenia. Widespread petechial hemorrhages were noted 10 to 25 days after naproxen initiation in 3 individuals. All 3 adults had improvement in their platelet counts from 3 to 8 x109/L to within the normal concentration range 5 to 7 days after naproxen discontinuation and prednisone receipt. The sera from each patient had antibodies against platelets in the presence of naproxen glucuronide. Anemia has been noted in less than 3% of patients during naproxen trials. Other hematologic effects (less than 1%) due to naproxen include aplastic anemia, hemolytic anemia, thrombocytopenia, prolonged bleeding time, abnormal red and white blood cells, agranulocytosis, leukopenia, eosinophilia, and granulocytopenia. Aplastic anemia, hemolytic anemia, eosinophilia, leukopenia, and granulocytopenia have been noted in postmarketing reports. Rectal bleeding, lymphadenopathy, and pancytopenia were noted in less than 1% of patients taking NSAIDs. Blood loss from gastrointestinal damage caused by naproxen is usually not significant. However, blood loss over time can result in iron deficiency anemia. Patients on prolonged therapy should undergo regular blood monitoring. Interpretation of the hematocrit and hemoglobin should be considered in relation to the fluid status, as naproxen can cause fluid retention. 
The most common adverse CNS reactions with naproxen include headache (3% to 15%) and drowsiness (3% to 9%). Vertigo, lightheadedness, paresthesias, asthenia, and insomnia are reported in less than 3% of patients during naproxen trials. Dizziness has been reported in less than 3% to 9% of patients. Other CNS reactions occur less frequently (less than 1%), including depression, malaise, anxiety, hypertonia, nervousness, neuralgia, neuritis, amnesia, confusion, abnormal coordination, diplopia, emotional lability, subdural hematoma, muscle paralysis, dream abnormalities, cognitive dysfunction, muscle weakness (myasthenia), and an inability to concentrate (impaired concentration). Adverse events noted in postmarketing reports include depression, dream abnormalities, insomnia, myalgia, muscle weakness, cognitive dysfunction, and seizures. Somnolence, tremor, coma, and hallucinations were noted in less than 1% of patients taking NSAIDs.  Overuse of drugs for treating acute headaches, including NSAIDs, may lead to medication overuse headache. Patients may experience migraine-like daily headaches or a significant increase in migraine attack frequency. Discontinuation of the overused drug and treatment of withdrawal symptoms (e.g., transient worsening of headache) may be necessary. Advise patients about the risks of medication overuse (e.g., use of naproxen for at least 15 days/month or any combination of therapy for at least 10 days/month) and encourage them to keep a written record of headache frequency and drug use. 
Visual impairment or disturbance, such as blurred vision, has been reported in < 3% of patients using naproxen. Other ocular adverse events reported in < 1% of patients included amblyopia, scleritis, cataracts, conjunctivitis, keratoconjunctivitis, lacrimation disorder, and ocular pain. Corneal opacification, papillitis, retrobulbar optic neuritis, and papilledema have been noted in post-marketing reports. 
Tinnitus (3—9%), hearing disturbances (< 3%), hearing loss / deafness (< 1%), ear disorder (< 1%), and otitis media (< 1%) have occurred with naproxen during clinical trials. Additionally, hearing impairment, has been noted in post-marketing reports.  Also, 6 cases of hearing loss have been reported in the literature. Two of the 6 patients had a post-treatment audiogram, which revealed a permanent severe bilateral sensorineural hearing loss. Of the other patients, 2 had recovery and 2 had no recovery of their hearing loss. Tinnitus and hearing loss have also occurred with the nonsteroidal anti-inflammatory drugs (NSAIDs) piroxicam and ketorolac. The hearing loss from NSAID usage is believed to be due to altered cochlear sensory cell function from tissue ischemia as a result of an imbalance between vasodilatory prostaglandins and vasoconstricting leukotrienes. Although no known morphologic changes are known to occur, hearing loss may be permanent. Coadministration of other ototoxic drugs, such as gentamicin or furosemide, may increase the risk of ototoxicity. Most ototoxic drugs have at least additive ototoxic interactions. Further, NSAIDs can be nephrotoxic, and impaired renal function can increase the ototoxic potential of NSAIDs. Patients taking long-term NSAIDs should be directly questioned about tinnitus and hearing loss.
Rare cases of jaundice (< 1%), hepatic necrosis (< 1%), and fatal hepatitis or hepatic failure have been reported in patients receiving naproxen. Hepatosplenomegaly (hepatomegaly and splenomegaly) and pancreatitis have been reported in < 1% of patients. Elevated hepatic enzymes occur in up to 15% of patients receiving NSAIDs. Elevations that are greater than three times the upper limit of normal have occurred in fewer than 1% of patients who received naproxen. Hepatic enzyme abnormalities may progress, stabilize, or regress with continued naproxen use. Hepatic abnormalities may be the result of hypersensitivity rather than direct toxicity. Evaluate patients with signs or symptoms of liver dysfunction such as an abnormal liver test result for the development of a more severe hepatic reaction. Naproxen should be discontinued if clinical signs or symptoms consistent with liver disease develop or if systemic manifestations such as eosinophilia or rash occur. 
Naproxen has been associated with aseptic meningitis (incidence of < 1% in clinical trials) but a causal relationship has not been established.  Ibuprofen has been the most common NSAID implicated in this adverse reaction; however, cases have been reported with sulindac, tolmetin, diclofenac, ketoprofen, rofecoxib, and piroxicam. Aseptic meningitis from one NSAID does not preclude use of another NSAID; most patients can be treated with another drug without incident. However, one patient with Sjogren's syndrome experienced aseptic meningitis after receipt of naproxen, ibuprofen, and rofecoxib at different times; aseptic meningitis developed about a week after each drug exposure, and the symptoms abated roughly 2 days following each drug cessation. The occurrence of aseptic meningitis is not related to NSAID chemical class or prostaglandin inhibition. A Type III or IV immunological hypersensitivity reaction is the proposed mechanism of action. Drug-induced aseptic meningitis usually occurs shortly after drug initiation but can occur after years of drug usage. Although NSAID-induced aseptic meningitis is primarily reported in patients with systemic lupus erythematosus (SLE), healthy patients and patients with other disease states such as ankylosing spondylitis, connective tissue disease, osteoarthritis, and rheumatoid arthritis have developed NSAID-induced aseptic meningitis. Symptoms of aseptic meningitis include confusion, drowsiness, general feeling of illness, severe headache, nausea, nuchal rigidity, and photophobia. As aseptic meningitis is a diagnosis of exclusion, the suspected drug should be discontinued and not restarted unless a rechallenge is desired.
Renal disease including renal function abnormality, interstitial nephritis, nephrotic syndrome, hematuria, glomerulonephritis, hyperkalemia, renal failure (unspecified), and renal papillary necrosis have occurred in fewer than 1% of patients receiving naproxen. Overall abnormal renal function has been reported in < 1% of patients receiving NSAIDs. It is well known that vasodilatory renal prostaglandins and the potent vasoconstrictor angiotensin II work in concert to maintain renal blood flow. Inhibition of prostaglandin synthesis by NSAIDs potentiates water reabsorption. Renal toxicity has been reported in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. Other genitourinary adverse events reported in < 1% of patients include dysmenorrhea, dysuria, nocturia, prostate disorder, breast carcinoma or neoplasm, urinary incontinence, kidney calculus, menorrhagia, metrorrhagia, nephrosclerosis, kidney pain (flank pain), pyuria, abnormal urine, increased urinary frequency, urinary retention, uterine spasm, vaginitis, and menstrual disorders. Edema occurred in < 1 % to 9% and peripheral edema was reported in < 3% of patients receiving naproxen. Oliguria, polyuria, proteinuria, glycosuria, azotemia, and albuminuria have been reported in < 1% of patients receiving NSAIDs.  Hyponatremia due to water intoxication has been reported with NSAID use.   Monitoring of the patient's fluid status and renal function is recommended.
NSAIDs, including naproxen, may cause an increased risk of serious cardiovascular thromboembolism, myocardial infarction (< 1%), and stroke, which can be fatal. Estimates of increased relative risk range from 10—50% or more, based on the drug and dose studied. The risk may increase with increased exposure, as measured in dose or duration. Significant cardiovascular risk has been observed within days to weeks of NSAID initiation. The relative increase in cardiovascular thrombotic events over baseline appears to be similar in patients with or without cardiovascular disease or risk factors for cardiovascular disease; however, patients with known cardiovascular disease or risk factors may be at greater risk because of a higher baseline risk of events. Hypertension was noted in < 3% of patients taking naproxen in clinical trials; in general, NSAIDs can lead to new onset or worsening hypertension, which may contribute to the increased incidence of cardiovascular events. Palpitations were noted in < 3% of patients taking naproxen in clinical trials. Adverse events noted in < 1% of patients included pulmonary edema, angina pectoris, coronary artery disease, deep thrombo-phlebitis, peripheral vasodilation, vascular anomaly, arrhythmia exacerbation, bundle-branch block, abnormal ECG, heart failure, hemorrhage (bleeding), migraine, aortic stenosis, syncope, vasculitis, and sinus tachycardia. Fluid retention caused by naproxen can elevate blood pressure, especially in patients with hypertension. Hypotension has been reported in < 1% of patients taking NSAIDs.  In adults (76% White, 14% Black) with stable hypertension (systolic < 150 mmHg) and normal renal function, the mean change from baseline in average 24-hour systolic pressure was -0.8 +/- 1.1 mmHg and diastolic pressure was -1 +/- 0.6 mmHg after 6 weeks of naproxen 500 mg twice daily. Blood pressure was measured every 20 minutes during 24-hour ambulatory monitoring, and no antihypertensive drug changes were allowed (all patients took at least an angiotensin converting enzyme inhibitor or an angiotensin-2 receptor blocker). Similar findings were obtained when blood pressure was measured in a clinic between 7 and 11 in the morning. Of the 101 patients, an increase in the systolic blood pressure of 0—10 mmHg occurred in 37%, an increase in 10—20 mmHg occurred in 7%, and a > 20 mmHg increase occurred in 2%. Furthermore, of 57 patients who had a baseline ambulatory systolic blood pressure < 135 mmHg, 11 had a reading of >= 135 mmHg at week 6. Inform patients of the signs and symptoms of CV events, and advise them to seek medical help immediately if such signs or symptoms occur.
The most frequent skin and soft tissue adverse events associated with naproxen include pruritus (less than 1% to 9%), skin eruptions (3% to 9%), rash (less than 1% to 9%), and ecchymosis (3% to 9%). Diaphoresis and purpura occur in less than 3% of patients. Other dermatologic reactions occur less frequently (less than 1%), including angiodermatitis, herpes simplex, xerosis, skin ulcer, acne vulgaris, alopecia, contact dermatitis, eczema, herpes zoster, nail disorder, skin necrosis, subcutaneous nodule, skin neoplasm, urticaria, photosensitivity reaction resembling porphyria cutanea tarda, epidermolysis bullosa (bullous rash), and photosensitive dermatitis. Erythema nodosum, fixed drug eruption, lichen planus-like eruption, pustular reaction, and systemic lupus erythematosus (lupus-like symptoms) were noted in postmarketing reports.  Three patients developed pseudoporphyria during treatment with over-the-counter naproxen 400 mg/day 4 to 5 times weekly for osteoarthritis for an unspecified length of time. The patients had skin fragility, blistering, tense bullae and/or shallow erosions predominantly on sun-exposed areas. Histological analyses were consistent with porphyria, but urine and plasma porphyrins were within normal limits. Skin lesions resolved within 1 to 6 months of naproxen discontinuation. No recurrences were seen during 15 to 34 months of follow-up. Serious adverse events such as toxic epidermal necrolysis (less than 1%), erythema multiforme (less than 1%), exfoliative dermatitis (less than 1% of NSAID patients), and Stevens-Johnson syndrome (less than 1%) can occur with naproxen without warning. Advise patients to discontinue the medication and contact their health care provider if erythema, rash, blisters, or related skin reactions develop. Chills, eosinophilic pneumonitis, vasculitis, and anaphylactoid reactions including anaphylactic shock and angioedema occurred in less than 1% of patients in clinical trials of naproxen. Dyspnea occurred in 3% to 9% of patients. 
Musculoskeletal adverse events that occurred in 3—9% of patients taking naproxen in clinical trials included back pain and pain. Muscle cramps (leg), myalgia, arthralgia, joint disorder, and tendon disorder were reported in < 3% of patients. Adverse events noted in < 1% of patients include bone disorder, spontaneous bone fractures, fibro-tendinitis, bone pain, ptosis, general muscle spasm, and bursitis. 
Hyperglycemia and thirst have been reported in less than 3% of patients during naproxen clinical trials. Other metabolic and nutritional adverse events reported in less than 1% of patients include hypoglycemia, hypercholesterolemia, metabolic alkalosis, dehydration, decreased glucose tolerance, hyperuricemia, and hypokalemia. 
Infectious adverse events reported during naproxen trials include general infection (3% to 9%), urinary tract infection (3% to 9%), influenza-like syndrome (10%), cystitis (less than 3%), abscess (less than 1%), pneumonia (less than 1%), and pyelonephritis (less than 1%). Adverse events related to NSAID therapy and occurring in less than 1% include infection, sepsis, and pneumonia. 
Respiratory adverse events that have been noted in naproxen clinical trials include pharyngitis (3—9%), rhinitis (3—9%), sinusitis (3—9%), bronchitis (< 3%), increased cough (< 3%), asthma or bronchospasm (< 1%), pulmonary disorder (< 1%), epistaxis (< 1%), respiratory distress (< 1%), and respiratory disorder (< 1%). Asthma and respiratory depression have been reported in < 1% of patients taking NSAIDs. 
General adverse events reported during naproxen clinical trials include fever (less than 3%), injury or accident (less than 3%), chest pain (unspecified) (less than 3%), nuchal rigidity (less than 1%), neck pain (less than 1%), enlarged abdomen (less than 1%), carcinoma (less than 1%), cellulitis (less than 1%), LE syndrome (less than 1%), mucous membrane disorder (less than 1%), and pelvic pain (less than 1%). Death was reported in less than 1% of patients taking NSAIDs. 
NSAIDs, such as naproxen, may delay or prevent prostaglandin-mediated rupture of ovarian follicles, which has been associated with reversible infertility. Small studies of women treated with NSAIDs demonstrated a reversible delay in ovulation. Consider withdrawal of NSAIDs in women who have difficulties conceiving or who are undergoing infertility evaluation. Female infertility has been noted in post-marketing reports for naproxen. 
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), a multi-organ hypersensitivity reaction, has occurred with NSAIDs. Some of these events have been life-threatening or fatal. DRESS typically presents as fever, rash, and/or lymphadenopathy in conjunction with other organ system involvement including hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Early manifestations such as fever and lymphadenopathy may be present without evidence of a rash. Discontinue the NSAID in patients presenting with such signs and symptoms in whom an alternative etiology cannot be identified.
Naproxen is contraindicated in patients with known salicylate hypersensitivity or NSAID hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) and in patients with a history of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients. A subpopulation of patients with asthma may have aspirin-sensitive asthma, which may include chronic rhinosinusitis complicated by nasal polyps, severe and potentially fatal acute bronchospasm, and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported, naproxen is contraindicated in patients with aspirin-sensitive asthma. When naproxen is used in patients with preexisting asthma without known aspirin sensitivity, monitor patients for changes in the signs and symptoms of asthma. Naproxen is contraindicated in patients with previous serious rash or skin reactions to NSAIDs. The use of NSAIDs, including naproxen, may cause serious and potentially fatal skin reactions including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Educate patients about the signs and symptoms of serious skin reactions and to discontinue the use of naproxen at the first appearance of skin rash or hypersensitivity.
NSAIDs, including naproxen, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and GI perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Patients with a prior history of peptic ulcer disease and/or GI bleeding who use NSAIDs have a more than 10-fold increased risk for developing a GI bleed compared to patients without risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy, concomitant oral corticosteroids, anticoagulant therapy, aspirin, or selective serotonin reuptake inhibitors (SSRIs), tobacco smoking, ethanol ingestion, older age, and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease or coagulopathy are at increased risk for GI bleeding. To minimize GI risks in NSAID-treated patients, use the lowest effective dosage for the shortest possible duration, and avoid administration of more than 1 NSAID at a time. In the setting of concomitant low-dose aspirin use for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding. Avoid NSAID use in higher risk populations unless the benefits are expected to outweigh the risks of bleeding; consider alternate therapy other than NSAIDs in higher risk patients as well as those with active GI bleeding. Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy.
Naproxen is contraindicated in the setting of coronary artery bypass graft surgery (CABG). An increased incidence of thromboembolism, including myocardial infarction or stroke, was found through analysis of data regarding the use of a COX-2 selective nonsteroidal anti-inflammatory drug (NSAID) for the treatment of pain in the first 10 to 14 days after CABG surgery. Naproxen, like all NSAIDs, may exacerbate heart failure and hypertension and may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. Avoid the use of naproxen in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If naproxen is used in patients with severe heart failure, monitor for signs of worsening heart failure. Trials demonstrated an approximately doubling of hospitalizations for heart failure in patients treated with selective and nonselective NSAIDs compared to placebo-treated patients. Additionally, fluid retention and edema have been observed with NSAID use. Consider the sodium content of naproxen sodium in patients requiring severe sodium restriction. Caution is recommended when administering naproxen to patients with cardiac disease, cardiomyopathy, cardiac arrhythmias (e.g., tachycardia), significant coronary artery disease (including acute myocardial infarction, angina, or history of myocardial infarction), peripheral vascular disease, cerebrovascular disease (e.g., stroke, transient ischemic attack), hypertension, pre-existing renal disease, or fluid retention. Closely monitor blood pressure during naproxen receipt. Use the lowest effective dose for the shortest duration possible to minimize the potential risk for an adverse cardiovascular event. Inform patients to seek immediate medical attention if they experience any signs or symptoms of a cardiovascular thrombotic event. Myocardial infarction or stroke can occur as early as the first weeks of using a NSAID, and risk may increase with higher doses and longer duration of use. NSAIDs may increase the risk of a cardiovascular thrombotic event in patients with or without underlying heart disease or risk factors for heart disease. Patients with known heart disease or risk factors appear to have a greater likelihood of an event after NSAID use, likely due to a higher baseline risk. While comprehensive data regarding relative cardiovascular safety of any particular NSAID compared to other NSAIDs is not available, celecoxib 100 mg twice daily was shown to be non-inferior to ibuprofen 600 to 800 mg 3 times daily or naproxen 375 to 500 mg twice daily for the composite endpoint of cardiovascular death, nonfatal MI, and nonfatal stroke in osteoarthritis or rheumatoid arthritis adult patients with or at high risk for cardiovascular disease. Celecoxib had negligible effect on average 24-hour systolic blood pressure, while average 24-hour systolic pressures increased by 3.7 mmHg and 1.6 mmHg in patients taking ibuprofen and naproxen, respectively. There is no consistent evidence that concomitant use of aspirin mitigates the increased risk for cardiovascular thrombotic events. Guidelines state NSAIDs should not be administered to patients presenting with and hospitalized for ST-elevation myocardial infarction (STEMI) due to increased risk of mortality, reinfarction, hypertension, heart failure, and myocardial rupture associated with their use. Observational data from a national registry demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, cardiovascular-related death, and all-cause mortality beginning the first week of treatment. An increased relative risk of death in NSAID users continued during the follow-up period of 4 years. Data demonstrate that patients treated with NSAIDs were more likely to die in the first year following a myocardial infarction compared to those not treated with NSAIDs.
Correct volume status in dehydrated or hypovolemic patients before starting naproxen. Monitor renal function in patients with renal impairment, heart failure, dehydration, or hypovolemia during naproxen use. Avoid naproxen use in patients with advanced renal disease or renal failure unless the benefits are expected to outweigh the risk of worsening renal function. If naproxen is used in patients with advanced renal disease, monitor patients for signs and symptoms of worsening renal function. Naproxen is not recommended for use in patients with moderate to severe and severe renal impairment (CrCl less than 30 mL/minute). Renal toxicity has been observed in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, NSAID use may cause a dose-dependent reduction in prostaglandin formation, and secondarily, renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and angiotensin converting enzyme inhibitors or angiotensin receptor blockers, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.
Use caution when high naproxen doses are required in patients with chronic alcoholic hepatic disease and other diseases with decreased or abnormal plasma proteins (i.e., hypoalbuminemia). Dosage adjustment may be required; use the lowest effective dose. In these patients, the total plasma concentration of naproxen may be reduced, but the plasma concentration of unbound naproxen is increased. Additionally, patients with advanced liver disease are at increased risk for gastrointestinal bleeding.
Monitor hemoglobin values periodically in patients with initial hemoglobin values of 10 g/dL or less who are to receive long-term NSAID therapy. Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis.
Naproxen cannot be expected to substitute for corticosteroid therapy or treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Taper corticosteroid therapy slowly if a decision is made to discontinue corticosteroids for patients on prolonged corticosteroid therapy; observe the patient closely for any adverse effects, including adrenal insufficiency and exacerbation of symptoms of arthritis. Additionally, concomitant use of oral corticosteroid therapy may increase the risk of GI bleeding in patients treated with NSAIDs.
Geriatric adults are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal (GI), and renal adverse reactions. Most spontaneous reports of fatal GI events are in the geriatric population. If the anticipated benefit outweighs these potential risks, start naproxen therapy at the low end of the dosage range and monitor for adverse effects. Use caution when high doses are required; some dosage adjustment may be necessary for older adults. Use the lowest effective dose. According to the Beers Criteria, NSAIDs are considered potentially inappropriate medications (PIMs) in the older adult as NSAIDs may cause new or worsening gastric and duodenal ulcers, and there is an increased risk of GI bleeding and peptic ulcer disease in high-risk groups including those greater than 75 years of age, or those taking systemic corticosteroids, anticoagulants, or antiplatelet medications. The risk of GI ulcers, gross bleeding, or perforation is cumulative with continued use. Avoid the chronic use of NSAIDs in high-risk persons including those with a history of gastric or duodenal ulcers, unless other alternatives are not effective, and the person can take a gastroprotective agent. The use of a gastroprotective agent, like a proton pump inhibitor or misoprostol, reduces but does not eliminate GI risks. NSAIDs may also increase blood pressure and induce kidney injury. Avoid use of NSAIDs in geriatric adults with the following conditions due to the potential for symptom exacerbation or adverse effects: symptomatic heart failure (fluid retention, symptom exacerbation) or chronic kidney disease Stage 4 or higher (CrCl less than 30 mL/minute) (acute kidney injury, further decline of renal function). Use with caution in persons with asymptomatic heart failure.
Naproxen may cause laboratory test interference. Naproxen may decrease platelet aggregation and prolong bleeding time. Consider this effect when bleeding times are determined. The administration of naproxen may also result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay. Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used. Additionally, naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA). Consider this effect when urinary 5-hydroxy indoleacetic acid is determined.
Avoid naproxen use during the third trimester of pregnancy (starting at 30 weeks of gestation) due to the risk of premature closure of the fetal ductus arteriosus and persistent pulmonary hypertension in the neonate. If NSAID treatment is deemed necessary between 20 to 30 weeks of pregnancy, limit use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if NSAID treatment extends beyond 48 hours. Discontinue the NSAID if oligohydramnios occurs and follow up according to clinical practice. Use of NSAIDs around 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. Observational data regarding embryofetal risks of NSAID use during the first trimester is inconclusive. There are no adequate and well-controlled studies of naproxen in pregnant women. Naproxen is not recommended in labor and obstetric delivery because naproxen may adversely affect fetal circulation and inhibit uterine contractions, which may increase the risk of uterine hemorrhage.
Naproxen is excreted into breast milk in concentrations approximately equivalent to 1% of the maximal maternal plasma concentrations. Consider the developmental and health benefits of breast-feeding along with the need for naproxen and any potential adverse effects on the breastfed infant from naproxen or the underlying condition.  Naproxen use is usually considered compatible with breast-feeding; other alternative analgesic and antiinflammatory drugs considered to be usually compatible with breast-feeding include acetaminophen and ibuprofen.
NSAIDs, such as naproxen, may pose a reproductive risk by delaying or preventing prostaglandin-mediated rupture of ovarian follicles, which has been associated with reversible infertility. Small studies of women treated with NSAIDs demonstrated a reversible delay in ovulation. Consider withdrawal of NSAIDs in women who have difficulties conceiving or who are undergoing infertility evaluation.
Mechanism of Action: Naproxen competitively inhibits both cyclooxygenase (COX) isoenzymes, COX-1 and COX-2, by blocking arachidonate binding resulting in analgesic, antipyretic, and anti-inflammatory pharmacologic effects. The enzymes COX-1 and COX-2 catalyze the conversion of arachidonic acid to prostaglandin G2 (PGG2), the first step of the synthesis prostaglandins and thromboxanes that are involved in rapid physiological responses. COX isoenzymes are also responsible for a peroxidase reaction, which is not affected by NSAIDs. In addition, NSAIDs do not suppress leukotriene synthesis by lipoxygenase pathways. COX-1 is constitutively expressed in almost all tissues, while COX-2 appears to only be constitutively expressed in the brain, kidney, bones, reproductive organs, and some neoplasms (e.g., colon and prostate cancers). COX-1 is responsible for prostaglandin synthesis in response to stimulation by circulating hormones, as well as maintenance of normal renal function, gastric mucosal integrity, and hemostasis. However, COX-2 is inducible in many cells in response to certain mediators of inflammation (e.g., interleukin-1, tumor necrosis factor, lipopolysaccharide, mitogens, and reactive oxygen intermediates).
•Anti-inflammatory Activity: The anti-inflammatory mechanism of naproxen is due to decreased prostaglandin synthesis via inhibition of COX-1 and COX-2. It appears that the anti-inflammatory effects may be primarily due to inhibition of the COX-2 isoenzyme. However, COX-1 is expressed at some sites of inflammation. COX-1 is expressed in the joints of rheumatoid arthritis or osteoarthritis patients, especially the synovial lining, and it is the primary enzyme of prostaglandin synthesis in human bursitis. Naproxen is slightly more selective for COX-1 than COX-2.
•Analgesic Activity: Naproxen is effective in cases where inflammation has caused sensitivity of pain receptors (hyperalgesia). It appears prostaglandins, specifically prostaglandins E and F, are responsible for sensitizing the pain receptors; therefore, naproxen has an indirect analgesic effect by inhibiting the production of further prostaglandins and does not directly affect hyperalgesia or the pain threshold.
•Antipyretic Activity: Naproxen promotes a return to a normal body temperature set point in the hypothalamus by suppressing the synthesis of prostaglandins, specifically PGE2, in circumventricular organs in and near the hypothalamus. Naproxen may mask fever in some patients, especially with high or chronic dosing.
•GI Effects: Gastrointestinal side effects of naproxen are primarily contributed to COX-1 inhibition; however, potential role of COX-2 inhibition in the GI tract has not been fully elucidated.
•Platelet Effects: The inhibition of platelet aggregation seen with naproxen is due to dose-dependent inhibition of COX-1 in platelets leading to decreased levels of platelet thromboxane A2 and an increase in bleeding time (see Adverse Reactions). The inhibition of platelet aggregation is reversible upon discontinuation of naproxen. This differs from aspirin, which irreversibly binds to COX-1 in platelets inhibiting this enzyme for the life of the cell. In an in vitro study, naproxen inhibited thromboxane production and platelet aggregation by 88% for up to 8 hours. Naproxen inhibited COX-1 (measured as thromboxane B2 generation in clotting whole blood) to a greater extent as compared to ibuprofen, diclofenac, or meloxicam (94.9%, 88.7%, 49.5%, and 53.3%, respectively). Clinically, naproxen may provide some cardioprotection benefits. However, naproxen produces less consistent inhibition of thromboxane A2 than low-dose aspirin, and in clinical trials, the cardioprotective effects of naproxen have been inconsistent.
•Renal Effects: In the kidney, prostaglandins, produced by both COX-1 and COX-2, are important regulators of sodium and water reabsorption through PGE2 and of renal function and hemodynamics via PGI2 in response to vasoconstrictive factors (e.g., endothelin-1, a factor that increases peripheral vascular resistance) and through effects on the renin-angiotensin system. In conditions where renal blood flow is dependent upon prostaglandin synthesis, administration of NSAIDs can result in significant decreases in renal blood flow leading to acute renal failure. In addition, alterations in sodium and water reabsorption may worsen increased blood pressure, which can be significant in selected individuals.
•Bone Effects: Nonsteroidal anti-inflammatory drugs appear to suppress bone formation via inhibition of COX-2. In vivo data from rabbits revealed a significant reduction of bone growth with both naproxen and rofecoxib as compared with placebo. Bone resorption does not appear to be a mechanism that leads to decreased net bone formation, as the number of CD51 positive osteoclast-like cells per section was decreased with either NSAID as compared with drinking water alone. As determined from in vitro data, NSAIDs appear to arrest the osteoblast cell cycle at the G(0)/G(1) phase and induce cytotoxicity and cell death of osteoblasts primarily by apoptosis rather than by necrosis.
Naproxen is administered orally. It is more than 99% bound to albumin. At doses more than 500 mg/day, a less than proportional increase in plasma concentrations occurs due to increased clearance because of saturation of plasma protein binding. It is extensively metabolized in the liver to 6-O-desmethyl naproxen. Both naproxen and 6-O-desmethyl naproxen are further metabolized to their respective acylglucoronide conjugated metabolites. Urinary excretion is the predominant elimination pathway. Approximately 95% of naproxen is excreted in the urine with less than 1% as unchanged drug, less than 1% as 6-O-desmethyl naproxen, and 66% to 92% as their conjugates. Small amounts, 3% or less of an administered dose, is excreted in the feces. The naproxen anion has a plasma half-life of 12 to 17 hours.
Affected cytochrome P450 isoenzymes and drug transporters: CYP1A2, CYP2C8, CYP2C9
Naproxen is a substrate of the hepatic cytochrome isoenzymes CYP1A2, CYP2C8, and CYP2C9; CYP2C9 appears to be the main substrate pathway.
The different dosage forms of naproxen are bioequivalent in terms of extent of absorption (AUC) and peak concentration; however, the products do differ in their pattern of absorption. Naproxen and naproxen sodium are rapidly and completely absorbed from the GI tract. Onset of pain relief can be within 1 hour in patients taking naproxen and 30 minutes in patients taking naproxen sodium. The analgesic effect has been found to last for up to 12 hours. Peak plasma concentrations of naproxen are achieved 2 to 4 hours and 1 to 2 hours after ingestion of naproxen and naproxen sodium, respectively. The difference in rates between the 2 products is due to the increased aqueous solubility of the sodium salt of naproxen. The enteric polymer coating for enteric-coated naproxen dissolves above pH 6. Enteric-coated naproxen dissolves primarily in the small intestine rather than in the stomach, so the absorption of the drug is delayed until the stomach is emptied. When enteric-coated naproxen was given to fasted subjects, peak plasma concentrations were achieved about 4 to 6 hours after the first dose (range: 2 to 12 hours). When enteric-coated naproxen was given with food, peak plasma concentrations were achieved in about 12 hours (range: 4 to 24 hours). The presence of food prolonged the time the tablets remained in the stomach, time to first detectable serum naproxen concentrations, and time to maximal naproxen concentrations, but did not affect peak naproxen concentrations. The elimination half-life of naproxen is unchanged across products ranging from 12 to 17 hours. Steady-state concentrations are reached in 4 to 5 days.
Naproxen pharmacokinetics have not been determined in patients with hepatic insufficiency. In patients with chronic alcoholic hepatic disease and other diseases with decreased or abnormal plasma proteins (i.e., hypoalbuminemia), the total plasma concentration of naproxen may be reduced, but the plasma concentration of unbound naproxen is increased.
Naproxen pharmacokinetics have not been determined in patients with renal insufficiency. Naproxen metabolites may accumulate in the presence of renal insufficiency. Elimination of naproxen is decreased in patients with severe renal impairment.
In pediatric patients aged 5 to 16 years with arthritis, plasma naproxen concentrations after a single naproxen suspension 5 mg/kg dose were found to be similar to those in normal adults after a 500 mg dose. The terminal half-life appears to be similar in pediatric and adult patients.
Although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly, although the unbound fraction is less than 1% of the total naproxen concentration. Unbound trough naproxen concentrations in elderly subjects have been reported to range from 0.12% to 0.19% of total naproxen concentration, compared with 0.05% to 0.075% in younger subjects. The clinical significance of this finding is unclear.
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