NAPROXEN SODIUM

Naproxen Sodium Controlled-Release Tablets is a nonsteroidal anti-inflammatory drug, available as controlled-release tablets in 375 mg strength for oral administration. The chemical name is 2-naphthaleneacetic acid, 6-methoxy-α-methyl-sodium salt, (S)-. The molecular weight is 252.24. Its molecular formula is C 14 H 13 NaO 3 , and it has the following chemical structure. Naproxen sodium is an odorless crystalline powder, white to creamy in color. It is soluble in methanol and water. Naproxen Sodium Controlled-Release Tablets contain 412.5 mg of naproxen sodium, equivalent to 375 mg of naproxen, and 37.5 mg sodium. Each Naproxen Sodium Controlled-Release Tablet also contains the following inactive ingredients: ammoniomethacrylate copolymer Type A, ammoniomethacrylate copolymer Type B, citric acid, crospovidone, magnesium stearate, methacrylic acid copolymer Type A, microcrystalline cellulose, povidone, and talc. The tablet coating contains hydroxypropyl methylcellulose, polyethylene glycol, and titanium dioxide. The following chemical structure for Naproxen Sodium Controlled-Release Tablets is a nonsteroidal anti-inflammatory drug, available as controlled-release tablets in 375 mg strength for oral administration. The chemical name is 2-naphthaleneacetic acid, 6-methoxy--methyl-sodium salt, (S)-. The molecular weight is 252.24. Its molecular formula is C14H13NaO3.

Naproxen Sodium Controlled-Release Tablets are indicated for the treatment of: rheumatoid arthritis (RA) osteoarthritis (OA) ankylosing spondylitis (AS) tendinitis, bursitis acute gout primary dysmenorrhea (PD) the relief of mild to moderate pain [ see Warnings and Precautions ( 5 ) ]. Naproxen Sodium Controlled-Release Tablets is a nonsteroidal anti-inflammatory drug indicated for the treatment of: rheumatoid arthritis (RA)( 1 ) osteoarthritis (OA)( 1 ) ankylosing spondylitis (AS)( 1 ) tendinitis, bursitis ( 1 ) acute gout ( 1 ) primary dysmenorrhea (PD)( 1 ) the relief of mild to moderate pain ( 1 )

Use the lowest effective dosage for shortest duration consistent with individual patient treatment goals ( 2 ) RA, OA, and AS: The dosage is two 375 mg or 500 mg tablets once daily, or one 750 mg tablet once daily. Management of Pain, PD, and Acute Tendinitis and Bursitis: The dosage is two 500 mg tablets once daily. For patients requiring greater analgesic benefit, two 750 mg tablets or three 500 mg tablets may be used for a limited period. Thereafter, the total daily dose should not exceed two 500 mg tablets For the treatment of Acute Gout: The dosage is two to three 500 mg tablets once daily on the first day, followed by two 500 mg tablets once daily, until the attack has subsided. 2.1. General Dosing Instructions Carefully consider the potential benefits and risks of Naproxen Sodium Controlled-Release Tablets and other treatment options before deciding to use Naproxen Sodium Controlled-Release Tablets. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [ see Warnings and Precautions ( 5 ) ]. After observing the response to initial therapy with Naproxen Sodium Controlled-Release Tablets, the dose and frequency should be adjusted to suit an individual patient’s needs. 2.2 Rheumatoid Arthritis, Osteoarthritis, and Ankylosing Spondylitis The recommended starting dose of Naproxen Sodium Controlled-Release Tablets in adults is two Naproxen Sodium Controlled-Release 375 mg tablets (750 mg) once daily, one Naproxen Sodium Controlled-Release 750 mg (750 mg) once daily, or two Naproxen Sodium Controlled-Release 500 mg tablets (1,000 mg) once daily. Patients already taking naproxen 250 mg, 375 mg, or 500 mg twice daily (morning and evening) may have their total daily dose replaced with Naproxen Sodium Controlled-Release Tablets as a single daily dose. During long-term administration, the dose of Naproxen Sodium Controlled-Release Tablets may be adjusted up or down depending on the clinical response of the patient. In patients who tolerate lower doses of Naproxen Sodium Controlled-Release Tablets well, the dose may be increased to two Naproxen Sodium Controlled-Release 750 mg tablets (1,500 mg), or three Naproxen Sodium Controlled-Release 500 mg tablets (1,500 mg) once daily for limited periods when a higher level of anti-inflammatory/analgesic activity is required. When treating patients, especially at the higher dose levels, the physician should observe sufficient increased clinical benefit to offset the potential increased risk [ see Clinical Pharmacology ( 12.3 ) ]. The lowest effective dose should be sought and used in every patient. Symptomatic improvement in arthritis usually begins within one week; however, treatment for two weeks may be required to achieve a therapeutic benefit. 2.3 Management of Pain, Primary Dysmenorrhea, and Acute Tendinitis and Bursitis The recommended starting dose is two Naproxen Sodium Controlled-Release 500 mg tablets (1,000 mg) once daily. For patients requiring greater analgesic benefit, two Naproxen Sodium Controlled-Release 750 mg tablets (1,500 mg) or three Naproxen Sodium Controlled-Release 500 mg tablets (1,500 mg) may be used for a limited period. Thereafter, the total daily dose should not exceed two Naproxen Sodium Controlled-Release 500 mg tablets (1,000 mg). 2.4 Acute Gout The recommended dose on the first day is two to three Naproxen Sodium Controlled-Release 500 mg tablets (1,000 to 1,500 mg) once daily, followed by two Naproxen Sodium Controlled-Release 500 mg tablets (1,000 mg) once daily, until the attack has subsided. 2.5 Dosage Adjustments in Patients with Hepatic Impairment A lower dose should be considered in patients with renal or hepatic impairment or in elderly patients [ see Warnings and Precautions ( 5.3 ) ]. 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.

Naproxen Sodium Controlled-Release 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 )

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 ) ] The most frequent adverse events were headache (15%), followed by dyspepsia (14%), and flu syndrome (10%). ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, SA3, LLC at 1-888-495-6078 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical 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. As with all drugs in this class, the frequency and severity of adverse events depends on several factors: the dose of the drug and duration of treatment; the age, the sex, physical condition of the patient; any concurrent medical diagnoses or individual risk factors. The following adverse reactions are divided into three parts based on frequency and whether or not the possibility exists of a causal relationship between drug usage and these adverse events. In those reactions listed as “Probable Causal Relationship” there is at least one case for each adverse reaction where there is evidence to suggest that there is a causal relationship between drug usage and the reported event. The adverse reactions reported were based on the results from two double-blind controlled clinical trials of three months duration with an additional nine month open-label extension. A total of 542 patients received Naproxen Sodium Controlled-Release Tablets either in the double-blind period or in the nine month open-label extension. Of these 542 patients, 232 received Naproxen Sodium Controlled-Release Tablets, 167 were initially treated with Naprosyn ® and 143 were initially treated with placebo. Adverse reactions reported by patients who received Naproxen Sodium Controlled-Release Tablets are shown by body system. Those adverse reactions observed with naproxen but not reported in controlled trials with Naproxen Sodium Controlled-Release Tablets are italicized . The most frequent adverse events from the double-blind and open-label clinical trials were headache (15%), followed by dyspepsia (14%), and flu syndrome (10%). The incidence of other adverse events occurring in 3% to 9% of the patients are marked with an asterisk. Those reactions occurring in less than 3% of the patients are unmarked. Incidence greater than 1% ( probable causal relationship ) Body as a Whole—Pain (back)*, pain*, infection*, fever, injury (accident), asthenia, pain chest, headache (15%), flu syndrome (10%). Gastrointestinal—Nausea*, diarrhea*, constipation*, abdominal pain*, flatulence, gastritis, vomiting, dysphagia, dyspepsia (14%), heartburn *, stomatitis . Hematologic—Anemia, ecchymosis. Respiratory—Pharyngitis*, rhinitis*, sinusitis*, bronchitis, cough increased. Renal—Urinary tract infection*, cystitis. Dermatologic—Skin rash*, skin eruptions *, ecchymoses *, purpura . Metabolic and Nutrition—Peripheral edema, hyperglycemia. Central Nervous System—Dizziness, paresthesia, insomnia, drowsiness *, lightheadedness . Cardiovascular—Hypertension, edema *, dyspnea *, palpitations . Musculoskeletal—Cramps (leg), myalgia, arthralgia, joint disorder, tendon disorder. Special Senses— Tinnitus *, hearing disturbances , visual disturbances . General— Thirst . Incidence less than 1% ( probable causal relationship ) Body as a Whole—Abscess, monilia, neck rigid, pain neck, abdomen enlarged, carcinoma, cellulitis, edema general, LE syndrome, malaise, mucous membrane disorder, allergic reaction, pain pelvic. Gastrointestinal—Anorexia, cholecystitis, cholelithiasis, eructation, GI hemorrhage, rectal hemorrhage, stomatitis aphthous, stomatitis ulcer, ulcer mouth, ulcer stomach, periodontal abscess, cardiospasm, colitis, esophagitis, gastroenteritis, GI disorder, rectal disorder, tooth disorder, hepatosplenomegaly, liver function abnormality, melena, ulcer esophagus, hematemesis , jaundice , pancreatitis , necrosis . Renal—Dysmenorrhea, dysuria, kidney function abnormality, nocturia, prostate disorder, pyelonephritis, carcinoma breast, urinary incontinence, kidney calculus, kidney failure, menorrhagia, metrorrhagia, neoplasm breast, nephrosclerosis, hematuria, pain kidney, pyuria, urine abnormal, urinary frequency, urinary retention, uterine spasm, vaginitis, glomerular nephritis, hyperkalemia, interstitial nephritis, nephrotic syndrome, renal disease, renal failure, renal papillary necrosis . Hematologic—Leukopenia, bleeding time increased, eosinophilia, abnormal RBC, abnormal WBC, thrombocytopenia, agranulocytosis , granulocytopenia . Central Nervous System—Depression, anxiety, hypertonia, nervousness, neuralgia, neuritis, vertigo, amnesia, confusion, co-ordination, abnormal diplopia, emotional lability, hematoma subdural, paralysis, dream abnormalities, inability to concentrate, muscle weakness . Dermatologic: Angiodermatitis, herpes simplex, dry skin, sweating, ulcer skin, acne, alopecia, dermatitis contact, eczema, herpes zoster, nail disorder, skin necrosis, subcutaneous nodule, pruritus, urticaria, neoplasm skin, photosensitive dermatitis, photosensitivity reactions resembling porphyria cutaneous tarda, epidermolysis bullosa. Special Senses—Amblyopia, scleritis, cataract, conjunctivitis, deaf, ear disorder, keratoconjunctivitis, lacrimation disorder, otitis media, pain eye. Cardiovascular—Angina pectoris, coronary artery disease, myocardial infarction, deep thrombophlebitis, vasodilation, vascular anomaly, arrhythmia, bundle branch block, abnormal ECG, heart failure right, hemorrhage, migraine, aortic stenosis, syncope, tachycardia, congestive heart failure . Respiratory—Asthma, dyspnea, lung edema, laryngitis, lung disorder, epistaxis, pneumonia, respiratory distress, respiratory disorder, eosinophilic pneumonitis . Musculoskeletal—Myasthenia, bone disorder, spontaneous bone fracture, fibrotendinitis, bone pain, ptosis, spasm general, bursitis. Metabolic and Nutrition—Creatinine increase, glucosuria, hypercholesteremia, albuminuria, alkalosis, BUN increased, dehydration, edema, glucose tolerance decrease, hyperuricemia, hypokalemia, SGOT increase, SGPT increase, weight decrease. General— Anaphylactoid reactions, angioneurotic edema, menstrual disorders, hypoglycemia, pyrexia (chills and fevers). Incidence less than 1% ( causal relationship unknown ) Other adverse reactions listed in the naproxen package label, but not reported by those who received Naproxen Sodium Controlled-Release Tablets are shown in italics. These observations are being listed as alerting information to the physician. Hematologic— Aplastic anemia, hemolytic anemia. Central Nervous System— Aseptic meningitis, cognitive dysfunction. Dermatologic— Epidermal necrolysis, erythema multiforme, Stevens-Johnson syndrome. Gastrointestinal— Non-peptic GI ulceration, ulcerative stomatitis. Cardiovascular— Vasculitis.

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 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: 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: Concomitant 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 a substitute 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, hydantoins, other NSAIDs, and aspirin. Intervention: Patients simultaneously receiving naproxen sodium and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required. Drug/Laboratory Test Interaction s 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 sodium be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used. U rinary 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 are determined. Drugs that Interfere with Hemostasis (e.g. warfarin, aspirin, SSRIs/SNRIs) : Monitor patients for bleeding who are concomitantly taking Naproxen Sodium Controlled-Release Tablets with drugs that interfere with hemostasis. Concomitant use of Naproxen Sodium Controlled-Release Tablets and analgesic doses of aspirin is not generally recommended ( 7 ) ACE Inhibitors, Angiotensin Receptor Blockers (ARB), or Beta-Blockers : Concomitant use with Naproxen Sodium Controlled-Release Tablets may diminish the antihypertensive effect of these drugs. Monitor blood pressure ( 7 ) ACE Inhibitors and ARBs : Concomitant use with Naproxen Sodium Controlled-Release Tablets in elderly, volume depleted, or those with renal impairment may result in deterioration of renal function. In such high risk patients, monitor for signs of worsening renal function ( 7 ) Diuretics : NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects ( 7 ) Digoxin : Concomitant use with Naproxen Sodium Controlled-Release Tablets can increase serum concentration and prolong half-life of digoxin. Monitor serum digoxin levels ( 7 )