Source: FDA, National Drug Code (US) Revision Year: 2021
NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS are contraindicated in the following patients:
Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all 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, patients with known CV 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. The increase in CV thrombotic risk has been observed most consistently at higher doses.
To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur.
There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as naproxen, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2)]
Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see Contraindications (4)]
Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up.
Avoid the use of NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If NAPROSYN Tablets, EC-NAPROSYN and ANAPROX DS are used in patients with a recent MI, monitor patients for signs of cardiac ischemia.
NSAIDs, including naproxen, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and 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.
Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3-6 months, and in about 2%-4% of patients treated for one year. However, even short-term NSAID therapy is not without risk.
Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; 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 and/or coagulopathy are at increased risk for GI bleeding.
Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported.
Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including naproxen.
Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS immediately, and perform a clinical evaluation of the patient.
NSAIDs, including NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS, can lead to new onset of hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)].
Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy.
The Coxib and traditional NSAID Trialists' Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death.
Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of naproxen may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug Interactions (7)].
Avoid the use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS is used in patients with severe heart failure, monitor patients for signs of worsening heart failure.
Since each ANAPROX DS tablet contains 50 mg of sodium (about 2 mEq per each 500 mg of naproxen), this should be considered in patients whose overall intake of sodium must be severely restricted.
Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury.
Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in 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 ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.
No information is available from controlled clinical studies regarding the use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS in patients with advanced renal disease. The renal effects of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS may hasten the progression of renal dysfunction in patients with preexisting renal disease.
Correct volume status in dehydrated or hypovolemic patients prior to initiating NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS [see Drug Interactions (7)]. Avoid the use of NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS is used in patients with advanced renal disease, monitor patients for signs of worsening renal function.
Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state.
Naproxen has been associated with anaphylactic reactions in patients with and without known hypersensitivity to naproxen and in patients with aspirin-sensitive asthma [see Contraindications (4) and Warnings and Precautions (5.8)]
Seek emergency help if an anaphylactic reaction occurs.
A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS are contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4)]. When NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.
NSAIDs, including naproxen, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS at the first appearance of skin rash or any other sign of hypersensitivity. NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS are contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)].
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS and evaluate the patient immediately.
Avoid use of NSAIDs, including NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS, in pregnant women at about 30 weeks of gestation and later. NSAIDs, including NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age.
Use of NSAIDs, including NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS, at about 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, for example, 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.
If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS treatment extends beyond 48 hours. Discontinue NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations (8.1)].
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. If a patient treated with NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS has any signs or symptoms of anemia, monitor hemoglobin or hematocrit.
NSAIDs, including NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin and other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)].
The pharmacological activity of NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.
Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [see Warnings and Precautions (5.2, 5.3, 5.6)].
Patients with initial hemoglobin values of 10g or less who are to receive long-term therapy should have hemoglobin values determined periodically.
Because of adverse eye findings in animal studies with drugs of this class, it is recommended that ophthalmic studies be carried out if any change or disturbance in vision occurs.
The following adverse reactions are discussed in greater detail in other sections of the labeling:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Adverse reactions reported in controlled clinical trials in 960 patients treated for rheumatoid arthritis or osteoarthritis are listed below. In general, reactions in patients treated chronically were reported 2 to 10 times more frequently than they were in short-term studies in the 962 patients treated for mild to moderate pain or for dysmenorrhea. The most frequent complaints reported related to the gastrointestinal tract.
A clinical study found gastrointestinal reactions to be more frequent and more severe in rheumatoid arthritis patients taking daily doses of 1500 mg naproxen compared to those taking 750 mg naproxen.
In controlled clinical trials with about 80 pediatric patients and in well-monitored, open-label studies with about 400 pediatric patients with polyarticular juvenile idiopathic arthritis treated with naproxen, the incidence of rash and prolonged bleeding times were greater, the incidence of gastrointestinal and central nervous system reactions were about the same, and the incidence of other reactions were lower in pediatric patients than in adults.
In patients taking naproxen in clinical trials, the most frequently reported adverse experiences in approximately 1% to 10% of patients were:
Gastrointestinal (GI) Experiences, including: heartburn*, abdominal pain*, nausea*, constipation*, diarrhea, dyspepsia, stomatitis
Central Nervous System: headache*, dizziness*, drowsiness*, lightheadedness, vertigo
Dermatologic: pruritus* (itching), skin eruptions*, ecchymoses*, sweating, purpura
Special Senses: tinnitus*, visual disturbances, hearing disturbances
Cardiovascular: edema*, palpitations
General: dyspnea*, thirst
* Incidence of reported reaction between 3% and 9%. Those reactions occurring in less than 3% of the patients are unmarked.
In patients taking NSAIDs, the following adverse experiences have also been reported in approximately 1% to 10% of patients.
Gastrointestinal (GI) Experiences, including: flatulence, gross bleeding/perforation, GI ulcers (gastric/duodenal), vomiting
General: abnormal renal function, anemia, elevated liver enzymes, increased bleeding time, rashes
The following are additional adverse experiences reported in <1% of patients taking naproxen during clinical trials.
Gastrointestinal: pancreatitis, vomiting
Hepatobiliary: jaundice
Hemic and Lymphatic: melena, thrombocytopenia, agranulocytosis
Nervous System: inability to concentrate
Dermatologic: skin rashes
The following adverse reactions have been identified during post approval use of naproxen. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
The following are additional adverse experiences reported in <1% of patients taking naproxen during clinical trials and through postmarketing reports. Those adverse reactions observed through postmarketing reports are italicized.
Body as a Whole: anaphylactoid reactions, angioneurotic edema, menstrual disorders, pyrexia (chills and fever)
Cardiovascular: congestive heart failure, vasculitis, hypertension, pulmonary edema
Gastrointestinal: inflammation, bleeding (sometimes fatal, particularly in the elderly), ulceration, perforation and obstruction of the upper or lower gastrointestinal tract. Esophagitis, stomatitis, hematemesis, colitis, exacerbation of inflammatory bowel disease (ulcerative colitis, Crohn’s disease).
Hepatobiliary: abnormal liver function tests, hepatitis (some cases have been fatal)
Hemic and Lymphatic: eosinophilia, leucopenia, granulocytopenia, hemolytic anemia, aplastic anemia
Metabolic and Nutritional: hyperglycemia, hypoglycemia
Nervous System: depression, dream abnormalities, insomnia, malaise, myalgia, muscle weakness, aseptic meningitis, cognitive dysfunction, convulsions
Respiratory: eosinophilic pneumonitis, asthma
Dermatologic: alopecia, urticaria, toxic epidermal necrolysis, erythema multiforme, erythema nodosum, fixed drug eruption, lichen planus, pustular reaction, systemic lupus erythematoses, bullous reactions, including Stevens-Johnson syndrome, photosensitive dermatitis, photosensitivity reactions, including rare cases resembling porphyria cutanea tarda (pseudoporphyria) or epidermolysis bullosa. If skin fragility, blistering or other symptoms suggestive of pseudoporphyria occur, treatment should be discontinued and the patient monitored.
Special Senses: hearing impairment, corneal opacity, papillitis, retrobulbar optic neuritis, papilledema
Urogenital: glomerular nephritis, hematuria, hyperkalemia, interstitial nephritis, nephrotic syndrome, renal disease, renal failure, renal papillary necrosis, raised serum creatinine
Reproduction (female): infertility
In patients taking NSAIDs, the following adverse experiences have also been reported in <1% of patients.
Body as a Whole: fever, infection, sepsis, anaphylactic reactions, appetite changes, death
Cardiovascular: hypertension, tachycardia, syncope, arrhythmia, hypotension, myocardial infarction
Gastrointestinal: dry mouth, esophagitis, gastric/peptic ulcers, gastritis, glossitis, eructation
Hepatobiliary: hepatitis, liver failure
Hemic and Lymphatic: rectal bleeding, lymphadenopathy, pancytopenia
Metabolic and Nutritional: weight changes
Nervous System: anxiety, asthenia, confusion, nervousness, paresthesia, somnolence, tremors, convulsions, coma, hallucinations
Respiratory: asthma, respiratory depression, pneumonia
Dermatologic: exfoliative dermatitis
Special Senses: blurred vision, conjunctivitis
Urogenital: cystitis, dysuria, oliguria/polyuria, proteinuria
See Table 1 for clinically significant drug interactions with naproxen.
Table 1. Clinically Significant Drug Interactions with naproxen:
| Drugs That Interfere with Hemostasis | |
|---|---|
| Clinical Impact: | • Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. |
| Intervention: | Monitor patients with concomitant use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.12)]. |
| Aspirin | |
| Clinical Impact: | A pharmacodynamic (PD) study has demonstrated an interaction in which lower dose naproxen (220mg/day or 220mg twice daily) interfered with the antiplatelet effect of low-dose immediate-release aspirin, with the interaction most marked during the washout period of naproxen [see Pharmacodynamics (12.2)]. There is reason to expect that the interaction would be present with prescription doses of naproxen or with enteric-coated low-dose aspirin; however, the peak interference with aspirin function may be later than observed in the PD study due to the longer washout period. Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2)]. |
| Intervention: | Because there may be an increased risk of cardiovascular events following discontinuation of naproxen due to the interference with the antiplatelet effect of aspirin during the washout period, for patients taking low-dose aspirin for cardioprotection who require intermittent analgesics, consider use of an NSAID that does not interfere with the antiplatelet effect of aspirin, or non-NSAID analgesics where appropriate. Concomitant use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.12)]. NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS are not substitutes for low dose aspirin for cardiovascular protection. |
| ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers | |
| Clinical Impact: | • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. |
| Intervention: | • During concomitant use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.6)]. • When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. |
| Diuretics | |
| Clinical Impact: | Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. |
| Intervention: | During concomitant use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)]. |
| Digoxin | |
| Clinical Impact: | The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin |
| Intervention: | During concomitant use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS and digoxin, monitor serum digoxin levels. |
| Lithium | |
| Clinical Impact: | NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. |
| Intervention: | During concomitant use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS and lithium, monitor patients for signs of lithium toxicity. |
| Methotrexate | |
| Clinical Impact: | Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). |
| Intervention: | During concomitant use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS and methotrexate, monitor patients for methotrexate toxicity. |
| Cyclosporine | |
| Clinical Impact: | Concomitant use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS and cyclosporine may increase cyclosporine’s nephrotoxicity. |
| Intervention: | During concomitant use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS and cyclosporine, monitor patients for signs of worsening renal function. |
| NSAIDs and Salicylates | |
| Clinical Impact: | Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)]. |
| Intervention: | The concomitant use of naproxen with other NSAIDs or salicylates is not recommended. |
| Pemetrexed | |
| Clinical Impact: | Concomitant use of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). |
| Intervention: | During concomitant use of NAPROSYN Tablets, EC-NAPROSYN or ANAPROX DS and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. |
| Antacids and Sucralfate | |
| Clinical Impact: | Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen. |
| Intervention: | Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS is not recommended. |
| Cholestyramine | |
| Clinical Impact: | Concomitant administration of cholestyramine can delay the absorption of naproxen. |
| Intervention: | Concomitant administration of cholestyramine with NAPROSYN Tablets, EC- NAPROSYN, or ANAPROX DS is not recommended. |
| Probenecid | |
| Clinical Impact: | Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly. |
| Intervention: | Patients simultaneously receiving NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS and probenecid should be observed for adjustment of dose if required. |
| Other albumin-bound drugs | |
| Clinical Impact: | Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin. |
| Intervention: | Patients simultaneously receiving NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required. |
| Bleeding times | |
|---|---|
| Clinical Impact: | Naproxen may decrease platelet aggregation and prolong bleeding time. |
| Intervention: | This effect should be kept in mind when bleeding times are determined. |
| Porter-Silber test | |
| Clinical Impact: | 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. |
| Intervention: | 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. |
| Urinary assays of 5-hydroxy indoleacetic acid (5HIAA) | |
| Clinical Impact: | Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA). |
| Intervention: | This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined. |
Use of NSAIDs, including NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS use between about 20 and 30 weeks of gestation, and avoid NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations, Data).
Use of NSAIDs, including NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus.
Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment.
Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies in rats, rabbits, and mice no evidence of teratogenicity or fetal harm when naproxen was administered during the period of organogenesis at doses 0.13, 0.26, and 0.6 times the maximum recommended human daily dose of 1500 mg/day, respectively [see Data]. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as naproxen, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses.
The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS, can cause premature closure of the fetal ductus arteriosus (see Data).
If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS, and follow up according to clinical practice (see Data).
There are no studies on the effects of NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS during labor or delivery. In animal studies, NSAIDS, including naproxen, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth.
There is some evidence to suggest that when inhibitors of prostaglandin synthesis are used to delay preterm labor, there is an increased risk of neonatal complications such as necrotizing enterocolitis, patent ductus arteriosus, and intracranial hemorrhage. Naproxen treatment given in late pregnancy to delay parturition has been associated with persistent pulmonary hypertension, renal dysfunction, and abnormal prostaglandin E levels in preterm infants. Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly starting at 30-weeks of gestation, or third trimester) should be avoided.
Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus.
Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with 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. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis.
Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain.
Reproduction studies have been performed in rats at 20 mg/kg/day (0.13 times the maximum recommended human daily dose of 1500 mg/day based on body surface area comparison), rabbits at 20 mg/kg/day (0.26 times the maximum recommended human daily dose, based on body surface area comparison), and mice at 170 mg/kg/day (0.6 times the maximum recommended human daily dose based on body surface area comparison) with no evidence of impaired fertility or harm to the fetus due to the drug.
The naproxen anion has been found in the milk of lactating women at a concentration equivalent to approximately 1% of maximum naproxen concentration in plasma.
The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS and any potential adverse effects on the breastfed infant from the NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS or from the underlying maternal condition.
Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including NAPROSYN Tablets, EC-NAPROSYN and ANAPROX DS, in women who have difficulties conceiving or who are undergoing investigation of infertility.
Safety and effectiveness in pediatric patients below the age of 2 years have not been established. Pediatric dosing recommendations for polyarticular juvenile idiopathic arthritis are based on well-controlled studies [see Dosage and Administration (2)]. There are no adequate effectiveness or dose-response data for other pediatric conditions, but the experience in polyarticular juvenile idiopathic arthritis and other use experience have established that single doses of 2.5 to 5 mg/kg as naproxen suspension, with total daily dose not exceeding 15 mg/kg/day, are well tolerated in pediatric patients over 2 years of age.
The hepatic and renal tolerability of long-term naproxen administration was studied in two double-blind clinical trials involving 586 patients. Of the patients studied, 98 patients were age 65 and older and 10 of the 98 patients were age 75 and older. NAPROXEN was administered at doses of 375 mg twice daily or 750 mg twice daily for up to 6 months. Transient abnormalities of laboratory tests assessing hepatic and renal function were noted in some patients, although there were no differences noted in the occurrence of abnormal values among different age groups.
Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.14)].
Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly. The clinical significance of this finding is unclear, although it is possible that the increase in free naproxen concentration could be associated with an increase in the rate of adverse events per a given dosage in some elderly patients. Caution is advised when high doses are required and some adjustment of dosage may be required in elderly patients. As with other drugs used in the elderly, it is prudent to use the lowest effective dose.
Experience indicates that geriatric patients may be particularly sensitive to certain adverse effects of nonsteroidal anti-inflammatory drugs. Elderly or debilitated patients seem to tolerate peptic ulceration or bleeding less well when these events do occur. Most spontaneous reports of fatal GI events are in the geriatric population [see Warnings and Precautions (5.2)].
Naproxen is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see Clinical Pharmacology (12.3)]. Geriatric patients may be at a greater risk for the development of a form of renal toxicity precipitated by reduced prostaglandin formation during administration of nonsteroidal anti-inflammatory drugs [see Warnings and Precautions (5.6)].
Naproxen-containing products are not recommended for use in patients with moderate to severe and severe renal impairment (creatinine clearance <30 mL/min) [see Warnings and Precautions (5.6), Clinical Pharmacology (12.3)].
Caution is advised when high doses are required and some adjustment of dosage may be required in these patients. It is prudent to use the lowest effective dose [see Clinical Pharmacology (12.3)].
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
