Drug Facts
Composition & Profile
Identifiers & Packaging
HOW SUPPLIED Naproxen Tablets USP: 375 mg: oval, light orange colored, biconvex, uncoated tablets, engraved with ‘G 32’ on one side and ‘375’ on the other side. Packaged in light-resistant bottles of 15,20,30,45,60 AND 90. NDC 63187-535-15 Bottle of 15 NDC 63187-535-20 Bottle of 20 NDC 63187-535-30 Bottle of 30 NDC 63187-535-45 Bottle of 45 NDC 63187-535-60 Bottle of 60 NDC 63187-535-90 Bottle of 90 Store at 15° to 30°C (59° to 86°F) in well-closed containers; dispense in light-resistant containers. Store at 15° to 30°C (59° to 86°F) in well-closed containers. ALEVE ® is a registered trademark of Bayer Healthcare LLC; 63187-535-30
- HOW SUPPLIED Naproxen Tablets USP: 375 mg: oval, light orange colored, biconvex, uncoated tablets, engraved with ‘G 32’ on one side and ‘375’ on the other side. Packaged in light-resistant bottles of 15,20,30,45,60 AND 90. NDC 63187-535-15 Bottle of 15 NDC 63187-535-20 Bottle of 20 NDC 63187-535-30 Bottle of 30 NDC 63187-535-45 Bottle of 45 NDC 63187-535-60 Bottle of 60 NDC 63187-535-90 Bottle of 90 Store at 15° to 30°C (59° to 86°F) in well-closed containers; dispense in light-resistant containers. Store at 15° to 30°C (59° to 86°F) in well-closed containers. ALEVE ® is a registered trademark of Bayer Healthcare LLC
- 63187-535-30
Overview
Naproxen USP is a proprionic acid derivative related to the arylacetic acid group of nonsteroidal anti-inflammatory drugs. The chemical names for naproxen USP and naproxen sodium USP are (S)-6-methoxy-α-methyl-2-naphthaleneacetic acid and (S)-6-methoxy-α-methyl-2-naphthaleneacetic acid, sodium salt, respectively. Naproxen USP and naproxen sodium USP have the following structures, respectively: Naproxen USP has a molecular weight of 230.26 and a molecular formula of C 14 H 14 O 3 . Naproxen sodium USP has a molecular weight of 252.23 and a molecular formula of C 14 H 13 NaO 3 . Naproxen USP is an odorless, white to off-white crystalline substance. It is lipid-soluble, practically insoluble in water at low pH and freely soluble in water at high pH. The octanol/water partition coefficient of naproxen USP at pH 7.4 is 1.6 to 1.8. Naproxen sodium USP is a white to creamy white, crystalline solid, freely soluble in water at neutral pH. Naproxen tablets USP are available as light orange colored tablets containing 375 mg of naproxen USP and light orange colored tablets for oral administration. The inactive ingredients are microcrystalline cellulose, croscarmellose sodium, iron oxides, povidone and magnesium stearate. chemical-structure
Indications & Usage
Carefully consider the potential benefits and risks of naproxen, naproxen sodium and other treatment options before deciding to use naproxen or naproxen sodium tablets. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS ). Naproxen as naproxen tablets or naproxen sodium tablets are indicated: • For the relief of the signs and symptoms of rheumatoid arthritis • For the relief of the signs and symptoms of osteoarthritis • For the relief of the signs and symptoms of ankylosing spondylitis • For the relief of the signs and symptoms of juvenile arthritis Naproxen as naproxen suspension is recommended for juvenile rheumatoid arthritis in order to obtain the maximum dosage flexibility based on the patient’s weight. Naproxen as naproxen tablets and naproxen sodium tablets are also indicated: • For relief of the signs and symptoms of tendonitis • For relief of the signs and symptoms of bursitis • For relief of the signs and symptoms of acute gout • For the management of pain • For the management of primary dysmenorrhea
Dosage & Administration
Carefully consider the potential benefits and risks of naproxen, naproxen sodium and other treatment options before deciding to use naproxen tablets and naproxen sodium tablets. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS ). After observing the response to initial therapy with naproxen or naproxen sodium, the dose and frequency should be adjusted to suit an individual patient's needs. Different dose strengths and formulations (ie, tablets, suspension) of the drug are not necessarily bioequivalent. This difference should be taken into consideration when changing formulation. Although naproxen and naproxen sodium circulate in the plasma as naproxen, they have pharmacokinetic differences that may affect onset of action. Onset of pain relief can begin within 30 minutes in patients taking naproxen sodium and within 1 hour in patients taking naproxen. The recommended strategy for initiating therapy is to choose a formulation and a starting dose likely to be effective for the patient and then adjust the dosage based on observation of benefit and/or adverse events. A lower dose should be considered in patients with renal or hepatic impairment or in elderly patients (see WARNINGS and PRECAUTIONS ). Geriatric Patients Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly. 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. Patients With Moderate to Severe Renal Impairment 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: Renal Effects ). Rheumatoid Arthritis, Osteoarthritis and Ankylosing Spondylitis Naproxen 250 mg or 375 mg or 500 mg twice daily twice daily twice daily Naproxen sodium 275 mg (naproxen 250 mg with 25 mg sodium) 550 mg (naproxen 500 mg with 50 mg sodium) twice daily twice daily During long-term administration, the dose of naproxen may be adjusted up or down depending on the clinical response of the patient. A lower daily dose may suffice for long-term administration. The morning and evening doses do not have to be equal in size and the administration of the drug more frequently than twice daily is not necessary. In patients who tolerate lower doses well, the dose may be increased to naproxen 1500 mg/day for limited periods of up to 6 months when a higher level of anti-inflammatory/analgesic activity is required. When treating such patients with naproxen 1500 mg/day, the physician should observe sufficient increased clinical benefits to offset the potential increased risk. The morning and evening doses do not have to be equal in size and administration of the drug more frequently than twice daily does not generally make a difference in response (see CLINICAL PHARMACOLOGY ). Juvenile Arthritis The recommended total daily dose of naproxen is approximately 10 mg/kg given in 2 divided doses (ie, 5 mg/kg given twice a day). Management of Pain, Primary Dysmenorrhea, and Acute Tendonitis and Bursitis The recommended starting dose is 550 mg of naproxen sodium as naproxen sodium tablet followed by 550 mg every 12 hours or 275 mg every 6 to 8 hours as required. The initial total daily dose should not exceed 1375 mg of naproxen sodium. Thereafter, the total daily dose should not exceed 1100 mg of naproxen sodium. Because the sodium salt of naproxen is more rapidly absorbed, naproxen sodium tablets are recommended for the management of acute painful conditions when prompt onset of pain relief is desired. Naproxen may also be used for initial treatment of acute pain because absorption of naproxen is delayed compared to other naproxen-containing products (see CLINICAL PHARMACOLOGY , INDICATIONS AND USAGE ). Acute Gout The recommended starting dose is 750 mg of naproxen followed by 250 mg every 8 hours until the attack has subsided. Naproxen sodium may also be used at a starting dose of 825 mg followed by 275 mg every 8 hours.
Warnings & Precautions
WARNINGS Cardiovascular Effects Cardiovascular 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, myocardial infarction, and stroke, which can be fatal. All NSAIDS, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or 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 does increase the risk of serious GI events (see WARNINGS: Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation ). 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 (see CONTRAINDICATIONS ). Hypertension NSAIDs, including naproxen and naproxen sodium, can lead to onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including naproxen and naproxen sodium, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy. Congestive Heart Failure and Edema Fluid retention, edema, and peripheral edema have been observed in some patients taking NSAIDs. Naproxen and naproxen sodium should be used with caution in patients with fluid retention, hypertension, or heart failure. Since each naproxen sodium tablet contains 25 mg or 50 mg of sodium (about 1 mEq per each 250 mg of naproxen), this could be considered in patients whose overall intake of sodium must be severely restricted. Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation NSAIDs, including naproxen and naproxen sodium, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the 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 occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk. The utility of periodic laboratory monitoring has not been demonstrated, nor has it been adequately assessed. Only 1 in 5 patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population. To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered. Epidemiological studies, both of the case-control and cohort design, have demonstrated as association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. In two studies, concurrent use of an NSAID or aspirin potentiated the risk of bleeding (see PRECAUTIONS - Drug Interactions ). Although these studies focused on upper gastrointestinal bleeding, there is reason to believe that bleeding at other sites may be similarly potentiated. NSAIDs should be given with care to patients with a history of inflammatory bowel disease (ulcerative colitis, Crohn’s disease) as their condition may be exacerbated. Renal Effects 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 a nonsteroidal anti-inflammatory drug 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, hypovolemia, heart failure, liver dysfunction, salt depletion, those taking diuretics and angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), and the elderly. Discontinuation of nonsteroidal anti-inflammatory drug therapy is usually followed by recovery to the pretreatment state (see WARNINGS: Advanced Renal Disease ). Advanced Renal Disease No information is available from controlled clinical studies regarding the use of naproxen or naproxen sodium in patients with advanced renal disease. Therefore, treatment with naproxen and naproxen sodium is not recommended in these patients with advanced renal disease. If naproxen or naproxen sodium therapy must be initiated, close monitoring of the patient's renal function is advisable and patients should be adequately hydrated. Anaphylactoid Reactions As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to naproxen or naproxen sodium. Naproxen and naproxen sodium should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see CONTRAINDICATIONS and PRECAUTIONS: Preexisting Asthma ). Emergency help should be sought in cases where an anaphylactoid reaction occurs. Anaphylactoid reactions, like anaphylaxis, may have a fatal outcome. Skin Reactions NSAIDs, including naproxen and naproxen sodium, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity. Pregnancy In late pregnancy, as with other NSAIDs, naproxen and naproxen sodium should be avoided because it may cause premature closure of the ductus arteriosus.
Boxed Warning
Cardiovascular Risk • NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk (see WARNINGS ). • Naproxen as naproxen tablets or naproxen sodium tablets is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS ). Gastrointestinal Risk • NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events (see WARNINGS ).
Contraindications
Naproxen and naproxen sodium are contraindicated in patients with known hypersensitivity to naproxen and naproxen sodium. Naproxen and naproxen sodium should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients (see WARNINGS: Anaphylactoid Reactions and PRECAUTIONS: Preexisting Asthma ). Naproxen and naproxen sodium are contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS ).
Adverse Reactions
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 (see CLINICAL PHARMACOLOGY ). In controlled clinical trials with about 80 pediatric patients and in well-monitored, open-label studies with about 400 pediatric patients with juvenile arthritis treated with naproxen, the incidence of rash and prolonged bleeding times were increased, 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 are: 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 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, pancreatitis, vomiting, colitis, exacerbation of inflammatory bowel disease (ulcerative colitis, Crohn’s disease) Hepatobiliary: jaundice, abnormal liver function tests, hepatitis (some cases have been fatal) Hemic and Lymphatic: eosinophilia, leucopenia, melena, thrombocytopenia, agranulocytosis, granulocytopenia, hemolytic anemia, aplastic anemia Metabolic and Nutritional: hyperglycemia, hypoglycemia Nervous System: inability to concentrate, depression, dream abnormalities, insomnia, malaise, myalgia, muscle weakness, aseptic meningitis, cognitive dysfunction, convulsions Respiratory: eosinophilic pneumonitis, asthma Dermatologic: alopecia, urticaria, skin rashes, 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
Drug Interactions
Angiotensin Converting Enzyme (ACE)-inhibitors/Angiotensin Receptor Blockers (ARBs) NSAIDs may diminish the antihypertensive effect of ACE-inhibitors, ARBs, or beta-blockers (including propanolol). Monitor patients taking NSAIDs concomitantly with ACE-inhibitors, ARBs, or beta blockers for changes in blood pressure. In addition, in patients who are elderly, volume-depleted (including those on diuretic therapy), or have compromised renal function, co-administration of NSAIDs with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. Monitor these patients closely for signs of worsening renal function Antacids and Sucralfate Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen. Aspirin When naproxen as naproxen tablets or naproxen sodium tablets is administered with aspirin, its protein binding is reduced, although the clearance of free naproxen or naproxen sodium is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of naproxen and naproxen sodium and aspirin is not generally recommended because of the potential of increased adverse effects. Cholestyramine As with other NSAIDs, concomitant administration of cholestyramine can delay the absorption of naproxen. Diuretics Clinical studies, as well as postmarketing observations, have shown that naproxen and naproxen sodium can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see WARNINGS: Renal Effects ), as well as to assure diuretic efficacy. Lithium NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity. Methotrexate NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. Naproxen, naproxen sodium and other nonsteroidal anti-inflammatory drugs have been reported to reduce the tubular secretion of methotrexate in an animal model. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate. Warfarin The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone. No significant interactions have been observed in clinical studies with naproxen and coumarin-type anticoagulants. However, caution is advised since interactions have been seen with other nonsteroidal agents of this class. The free fraction of warfarin may increase substantially in some subjects and naproxen interferes with platelet function. Selective Serotonin Reuptake Inhibitors (SSRIs) There is an increased risk of gastrointestinal bleeding when selective serotonin reuptake inhibitors (SSRIs) are combined with NSAIDs. Caution should be used when NSAIDs are administered concomitantly with SSRIs. Other Information Concerning Drug Interactions 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. Patients simultaneously receiving naproxen and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required. Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly.
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