Naproxen sodium tablets are indicated for: the relief of the signs and symptoms of:
rheumatoid arthritis
osteoarthritis
ankylosing spondylitis
Polyarticular Juvenile Idiopathic Arthritis
tendonitis
bursitis
acute gout the management of:
pain
primary dysmenorrhea Naproxen sodium tablets are non-steroidal anti-inflammatory drugs indicated for: the relief of the signs and symptoms of:
rheumatoid arthritis
osteoarthritis
ankylosing spondylitis
polyarticular juvenile idiopathic arthritis
tendonitis
bursitis
acute gout the management of:
pain
primary dysmenorrhea
Contraindications
Naproxen sodium tablets are contraindicated in the following patients:
Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to naproxen or any components of the drug product [see Warnings and Precautions (5.7 , 5.9 )]
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 [see Warnings and Precautions (5.7 , 5.8 )]
In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1) ]
Known hypersensitivity to naproxen or any components of the drug product ( 4 )
History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs ( 4 )
In the setting of CABG surgery ( 4 )
Warnings and precautions
Hepatotoxicity : Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop. ( 5.3 ) Hypertension : Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure. ( 5.4 , 7 ) Heart Failure and Edema: Avoid use of naproxen sodium in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure.
( 5.5 ) Renal Toxicity : Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of naproxen sodium in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function. ( 5.6 ) Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs. ( 5.7 ) Exacerbation of Asthma Related to Aspirin Sensitivity: Naproxen sodium is contraindicated in patients with aspirin-sensitive asthma.
Monitor patients with preexisting asthma (without aspirin sensitivity). ( 5.8 ) Serious Skin Reactions : Discontinue naproxen sodium at first appearance of skin rash or other signs of hypersensitivity. ( 5.9 ) Premature Closure of Fetal Ductus Arteriosus : Avoid use in pregnant women starting at 30 weeks gestation. ( 5.10 , 8.1 ) Hematologic Toxicity : Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia.
( 5.11 , 7 )
5.1Cardiovascular Thrombotic Events
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) ]. Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to14 days following CABG surgery found an increased incidence of myocardial infarction and stroke.
NSAIDs are contraindicated in the setting of CABG [see Contraindications (4) ]. Post-MI Patients 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 naproxen sodium in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If naproxen sodium is used in patients with a recent MI, monitor patients for signs of cardiac ischemia.
5.2Gastrointestinal Bleeding, Ulceration, and Perforation
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 to 6 months, and in about 2% to 4% of patients treated for one year. However, even short-term NSAID therapy is not without risk. Risk Factors for GI Bleeding, Ulceration, and Perforation 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.
Strategies to Minimize the GI Risks in NSAID-treated patients:
Use the lowest effective dosage for the shortest possible duration.
Avoid administration of more than one NSAID at a time.
Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs.
Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy.
If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue naproxen sodium until a serious GI adverse event is ruled out.
In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see Drug Interactions (7) ].
5.3Hepatotoxicity 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 naproxen sodium immediately, and perform a clinical evaluation of the patient.
5.4Hypertension
NSAIDs, including naproxen sodium 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)
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Interactions
See Table 2 for clinically significant drug interactions with naproxen. Table 2: 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 naproxen sodium 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 (5.11) ].
Aspirin Clinical Impact: A pharmacodynamic (PD) study has demonstrated an interaction in which lower dose naproxen (220 mg/day or 220 mg 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 Clinical Pharmacology (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.
Conomitant use of naproxen sodium and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions (5.11) ] . Naproxen sodium is 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 naproxen sodium and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. · During concomitant use of naproxen sodium 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 naproxen sodium 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 naproxen sodium 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 naproxen sodium 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 naproxen sodium and methotrexate, monitor patients for methotrexate toxicity.
Cyclosporine Clinical Impact: Concomitant use of naproxen sodium and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: During concomitant use of naproxen sodium 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 naproxen sodium and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of naproxen sodium 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 naproxen sodium is not recommended. Cholestyramine Clinical Impact: Concomitant administration of cholestyramine can delay the absorption of naproxen.
Intervention: Concomitant administration of cholestyramine with naproxen sodium 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 naproxen sodium 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, hydantoi
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Pregnancy and breastfeeding
8.1 Pregnancy Risk Summary Use of NSAIDs, including naproxen sodium, during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including naproxen sodium in pregnant women starting at 30 weeks of gestation (third trimester). There are no adequate and well-controlled studies of naproxen sodium in pregnant women. Data from observational studies regarding potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive.
In the general U.S. population, all clinically recognized pregnancies, regardless of drug exposure, have a background rate of 2 to 4% for major malformations, and 15 to 20% for pregnancy loss. 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. Clinical Considerations Labor or Delivery There are no studies on the effects of naproxen sodium during labor or delivery.
In animal studies, NSAIDS, including naproxen, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data Human Data 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.
Animal data 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.
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.
Adverse reactions
The following adverse reactions are discussed in greater detail in other sections of the labeling:
Cardiovascular Thrombotic Events [see Warnings and Precautions (5.1) ]
GI Bleeding, Ulceration, and Perforation [see Warnings and Precautions (5.2) ]
Hepatotoxicity [see Warnings and Precautions (5.3) ]
Hypertension [see Warnings and Precautions (5.4) ]
Heart Failure and Edema [see Warnings and Precautions (5.5) ]
Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.6) ]
Anaphylactic Reactions [see Warnings and Precautions (5.7) ]
Serious Skin Reactions [see Warnings and Precautions (5.9) ]
Hematologic Toxicity [see Warnings and Precautions (5.11) ] Most common adverse reactions to naproxen were dyspepsia, abdominal pain, nausea, headache, rash, ecchymosis, and edema. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1Clinical Trials Experience
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
6.2Postmarketing Experience
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.
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
At a glance
Brand name
Naproxen Sodium
Drug class
Propionic acid derivatives, Antiinflammatory products for vaginal administration
