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.[32122] [44091]

Esophagitis (< 1%) and esophageal ulceration (< 1%) have been reported in patients receiving NSAIDs, such as naproxen.[32122] [44091] 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 glucuronide, a metabolite of naproxen, may cause immune-mediated thrombocytopenia. Widespread petechial hemorrhages were noted 10 to 25 days after naproxen initiation in 3 subjects. All 3 adults had improvement in their platelet counts from 3 to 8 x 10⁹/L to within the normal concentration range 5 to 7 days after naproxen discontinuation and prednisone receipt. The sera from each subject had antibodies against platelets in the presence of naproxen glucuronide.[31419] Anemia and prolonged bleeding time have been reported with naproxen in 1% to 10% of subjects in trials. This may be related to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. NSAIDs may increase the risk of bleeding events. If an individual treated with an NSAID has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. Consider monitoring complete blood count (CBC) periodically in individuals on long-term NSAID treatment. Other hematologic effects (less than 1%) reported with naproxen include aplastic anemia, hemolytic anemia, thrombocytopenia, abnormal red and white blood cells, agranulocytosis, leukopenia, eosinophilia, and granulocytopenia. Lymphadenopathy and pancytopenia were noted in less than 1% of subjects taking NSAIDs. In controlled clinical trials with about 80 pediatric subjects and in open-label clinical studies with 400 pediatric subjects with polyarticular articular juvenile idiopathic arthritis, the incidence of prolonged bleeding time was greater in pediatric subjects compared to adults.[32122] [44091]

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.[32122] [44091] 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.[66767] [66803]

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.[32122] [44091]

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.[32122] [44091] 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.[27729] 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.[27726] 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.[32122] [44091]

Naproxen has been associated with aseptic meningitis (incidence of < 1% in clinical trials) but a causal relationship has not been established.[32122] [44091] 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.[27710] 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.[32122] [44091] Hyponatremia due to water intoxication has been reported with NSAID use.[33608] [33609] [33610] 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.[59937] 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.[32122] [44091] 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.[30756] Inform patients of the signs and symptoms of CV events, and advise them to seek medical help immediately if such signs or symptoms occur.

NSAIDs can cause serious and potentially fatal skin reactions, including exfoliative dermatitis, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and fixed drug eruption (FDE), which may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE). These serious events may occur without warning. Inform individuals about the signs and symptoms of serious skin reactions and instruct them to discontinue use of the NSAID at the first appearance of skin rash or any other sign of hypersensitivity. Diaphoresis (less than 3%), dyspnea (3% to 9%), ecchymosis (3% to 9%), pruritus (9% or less), purpura (less than 3%), rash (9% or less), and skin eruptions (3% to 9%) were reported with naproxen during clinical trials and probably causally related. Other allergic or dermatologic adverse reactions reported with naproxen in less than 1% of subjects during clinical trials or postmarketing and probably causally related include acne vulgaris, alopecia, anaphylactoid reactions, angiodermatitis, angioedema, bullous rash including SJS and FDE, chills, contact dermatitis, eczema, erythema multiforme, erythema nodosum, eosinophilic pneumonitis, exfoliative dermatitis, herpes simplex, herpes zoster, lichen planus-like eruption, nail disorder, photosensitive dermatitis, photosensitivity including rare cases resembling porphyria cutanea tarda (pseudoporphyria) or epidermolysis bullosa, pustular reaction, skin necrosis, skin neoplasm, skin ulcer, subcutaneous nodule, systemic lupus erythematoses (lupus-like symptoms), TEN, urticaria, and xerosis. If skin fragility, blistering, or other symptoms suggestive of pseudoporphyria occur, discontinue treatment and monitor the individual. Advise individuals to seek emergency help if an anaphylactic reaction occurs.[32122] [44091]

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.[32122] [44091]

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.[32122] [44091]

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.[32122] [44091]

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.[32122] [44091]

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.[32122] [44091]

NSAIDs may delay or prevent prostaglandin-mediated rupture of ovarian follicles, which has been associated with reversible infertility. Small studies with NSAIDs demonstrated a reversible delay in ovulation. Consider withdrawal of NSAIDs in people who may become pregnant who have difficulties conceiving or who are undergoing infertility evaluation.[32122] [44091]

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.[32122]

The pharmacological activity of NSAIDs in reducing inflammation, and possibly fever, may result in diagnostic test interference by diminishing the utility of these diagnostic signs in detecting infection. Naproxen may also cause laboratory test interference. Naproxen may cause decreased platelet aggregation and prolonged bleeding time. Keep this effect in mind when bleeding times are determined. Additionally, the administration of naproxen may 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 artificially 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. Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).[32122]

Naproxen is contraindicated in the setting of coronary artery bypass graft surgery (CABG). An increased incidence of myocardial infarction and stroke was found in clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days after CABG surgery. NSAIDs may increase the risk of serious cardiovascular events, which can be fatal.[32122] Guidelines recommend against NSAID use in individuals presenting with and hospitalized for ST-elevation myocardial infarction (STEMI) due to increased risk of mortality and cardiovascular (CV) complications associated with their use.[55688] Avoid NSAID use in individuals with a recent myocardial infarction unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If an NSAID is used in individuals with a recent myocardial infarction, monitor for signs of cardiac ischemia. Observational data from a national registry demonstrated that individuals treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-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 individuals treated with NSAIDs were more likely to die in the first year after a myocardial infarction compared to those not treated with NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease; however, individuals with known cardiovascular disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment with an NSAID; the increase in CV thrombotic risk has been observed most consistently at higher doses. Current evidence is insufficient to determine if the risk of an event is higher or lower for any particular NSAID compared to other NSAIDs. There is no consistent evidence that concomitant use of aspirin mitigates the increased risk for CV thrombotic events. To minimize the potential risk for an adverse CV event in NSAID-treated individuals, use the lowest effective dose for the shortest duration possible; remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. NSAIDs may worsen pre-existing hypertension, which may contribute to the increased incidence of CV events. Monitor blood pressure during NSAID treatment initiation and throughout therapy. Avoid NSAID use in individuals with severe heart failure, unless the benefits of treatment are expected to outweigh the risks. Monitor for signs of worsening heart failure if an NSAID is used in individuals with severe heart failure. Monitor renal function in individuals with heart failure during use of an NSAID. Data demonstrate an increased risk for myocardial infarction, hospitalization for heart failure, and death with NSAID use in individuals with heart failure.[32122]

Naproxen is contraindicated in individuals with aspirin exacerbated respiratory disease, which may include chronic rhinosinusitis complicated by nasal polyps, severe and potentially fatal acute bronchospasm, and/or intolerance to aspirin and other NSAIDs. When an NSAID is used in individuals with pre-existing asthma without known aspirin sensitivity, monitor for changes in the signs and symptoms of asthma.[32122]

Individuals with a prior history of GI bleeding and/or peptic ulcer disease who use NSAIDs had a more than 10-fold increased risk of developing a GI bleed compared to individuals without these risk factors. Individuals with advanced hepatic disease or bleeding disorder are also at increased risk for GI bleeding. Other risk factors for GI bleeding in individuals receiving NSAIDs include longer duration of NSAID therapy, concomitant use of oral corticosteroids, aspirin, anticoagulants, or SSRIs, tobacco smoking, ethanol ingestion, older age, and poor general health status. Coadministration with certain medications, specifically aspirin or other NSAIDs, is contraindicated due to the cumulative risk of inducing serious NSAID-related adverse events; concomitant use of ketorolac with aspirin or other NSAIDs increases the risk of GI toxicity, with little or no increase in efficacy. Serious gastrointestinal events, including bleeding, inflammation, perforation, and ulceration, can occur at any time and without warning symptoms in individuals receiving NSAIDs. To minimize the risk of an adverse GI event in NSAID-treated individuals, use the lowest effective NSAID dose for the shortest possible duration. Avoid concurrent administration of other NSAIDs; in the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor more closely for evidence of GI bleeding. Avoid NSAID use in individuals at higher risk for GI adverse events unless benefits are expected to outweigh the increased bleeding risk, and consider alternate therapies other than NSAIDs for those individuals and individuals with active GI bleeding. Monitor individuals for signs and symptoms of GI bleeding and ulceration during NSAID therapy.[32122]

Use caution when high doses of naproxen are used in individuals with hepatic impairment or hepatic failure; dosage adjustment may be necessary in these individuals. Use the lowest effective naproxen dose. Monitor renal function in individuals with hepatic impairment during use of an NSAID. NSAID use in individuals with hepatic failure in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion may precipitate renal decompensation. Advanced hepatic disease is also a risk factor for GI bleeding in individuals who use NSAIDs.[32122]

Naproxen is not recommended for use in individuals with moderate to severe and severe renal impairment or renal failure (CrCl less than 30 mL/minute). Avoid NSAID use in individuals with advanced renal disease, unless the benefits are expected to outweigh the risks of worsening renal function. If an NSAID is used in individuals with advanced renal disease, monitor for signs and symptoms of worsening renal function. Correct volume status in individuals with dehydration or hypovolemia prior to starting an NSAID. Monitor renal function in individuals with renal impairment, dehydration, or hypovolemia during use of an NSAID. NSAID use in individuals with renal impairment, dehydration, or hypovolemia in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion may precipitate renal decompensation. The renal effects of NSAIDs may hasten the progression of renal dysfunction in individuals with pre-existing renal disease.[32122]

Geriatric adults, compared to younger individuals, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the older adult outweighs these potential risks, start NSAID dosing at the low end of the dosing range, and monitor for adverse effects.[32122] According to the Beers Criteria, NSAIDs are considered potentially inappropriate medication (PIM) in geriatric adults. There is an increased risk of GI bleeding and peptic ulcer disease in high-risk groups including those older than 75 years, 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 individuals, including those with a history of gastric or duodenal ulcers, unless other alternatives are not effective, and the individual 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 individuals with asymptomatic heart failure.[63923]

Avoid the use of NSAIDs, such as naproxen, during pregnancy starting at 30 weeks gestation due to the risk of premature closure of the fetal ductus arteriosus. When 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 exceeds 48 hours. Discontinue the NSAID if oligohydramnios develops, and follow up according to clinical practice. Use of NSAIDs around 20 weeks gestation and later may also 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 cases, invasive neonatal procedures such as exchange transfusion or dialysis have been required. Observational data regarding other potential embryo-fetal risks of NSAID use during the first or second trimesters are inconclusive. Animal studies indicate that prostaglandins play an important role in endometrial blood flow, embryo implantation, and fetal kidney development. Inhibiting prostaglandin synthesis has been associated with increased pre- and post-implantation loss and impaired kidney development in animals at NSAID doses relevant to clinical use. The effects of naproxen on labor and obstetric delivery are unknown. In animal studies, NSAIDs inhibit prostaglandin synthesis, delay parturition, and increase the incidence of still birth.[32122]

Counsel people who may become pregnant about the reproductive risk associated with naproxen. NSAIDs may delay or prevent prostaglandin-mediated rupture of ovarian follicles, which has been associated with reversible infertility. Small studies with NSAIDs demonstrated a reversible delay in ovulation. Consider withdrawal of NSAIDs in people who may become pregnant who have difficulties conceiving or who are undergoing infertility evaluation.[32122]

Use naproxen with caution during breast-feeding. Limited data indicate naproxen is present in human milk in low concentrations (less than 1% of maternal serum levels), and that adverse effects in breastfed children are uncommon. There has been a report of naproxen possibly causing prolonged bleeding time, thrombocytopenia, and acute anemia in a 7-day-old infant exposed to the drug through the milk of a lactating individual also taking bacampicillin. Based on this report and the long half-life of naproxen, other agents may be preferred. Alternative analgesic and antiinflammatory drugs considered to be usually compatible with breast-feeding include acetaminophen and ibuprofen.[32122] [70364]