Naprelan

6 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 ( 5.12 ) ] The most frequent adverse events were headache (15%), followed by dyspepsia (14%), and flu syndrome (10%). ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Almatica Pharma, LLC at 1-877-447-7979 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 NAPRELAN Tablets either in the double-blind period or in the nine month open-label extension. Of these 542 patients, 232 received NAPRELAN Tablets, 167 were initially treated with Naprosyn ® and 143 were initially treated with placebo. Adverse reactions reported by patients who received NAPRELAN Tablets are shown by body system. Those adverse reactions observed with naproxen but not reported in controlled trials with NAPRELAN 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 NAPRELAN 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 .

4 CONTRAINDICATIONS NAPRELAN is 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 )

11 DESCRIPTION NAPRELAN (naproxen sodium) Controlled-Release Tablets is a nonsteroidal anti-inflammatory drug, available as controlled-release tablets in 375 mg, 500 mg, and 750 mg strengths 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. NAPRELAN Tablets contain 412.5 mg, 550 mg, or 825 mg of naproxen sodium, equivalent to 375 mg, 500 mg, and 750 mg of naproxen, and 37.5 mg, 50 mg, and 75 mg sodium respectively. Each NAPRELAN 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.

2 DOSAGE AND ADMINISTRATION 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 NAPRELAN and other treatment options before deciding to use NAPRELAN. 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 NAPRELAN, 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 NAPRELAN Tablets in adults is two NAPRELAN 375 mg tablets (750 mg) once daily, one NAPRELAN 750 mg (750 mg) once daily, or two NAPRELAN 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 NAPRELAN Tablets as a single daily dose. During long-term administration, the dose of NAPRELAN Tablets may be adjusted up or down depending on the clinical response of the patient. In patients who tolerate lower doses of NAPRELAN Tablets well, the dose may be increased to two NAPRELAN 750 mg tablets (1,500 mg), or three NAPRELAN 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 NAPRELAN 500 mg tablets (1,000 mg) once daily. For patients requiring greater analgesic benefit, two NAPRELAN 750 mg tablets (1,500 mg) or three NAPRELAN 500 mg tablets (1,500 mg) may be used for a limited period. Thereafter, the total daily dose should not exceed two NAPRELAN 500 mg tablets (1,000 mg). 2.4 Acute Gout The recommended dose on the first day is two to three NAPRELAN 500 mg tablets (1,000 to 1,500 mg) once daily, followed by two NAPRELAN 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.

1 INDICATIONS AND USAGE NAPRELAN 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 )] . NAPRELAN 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)

10 OVERDOSAGE Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [ see Warnings and Precautions ( 5.1 , 5.2 , 5.4 , 5.6 ) ]. A few patients have experienced seizures, but it is not clear whether or not these were drug-related. It is not known what dose of the drug would be life threatening. Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Hemodialysis does not decrease the plasma concentration of naproxen because of the high degree of its protein binding. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. For additional information about overdosage treatment contact a poison control center (1-800-222-1222).

7 DRUG INTERACTIONS 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 NAPRELAN 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 (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 cardio protection 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 NAPRELAN and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions ( 5.12 ) ]. NAPRELAN 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 NAPRELAN and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of NAPRELAN 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 NAPRELAN 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 NAPRELAN 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 NAPRELAN 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 NAPRELAN and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of NAPRELAN and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: During concomitant use of NAPRELAN 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 NAPRELAN and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of NAPRELAN 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 NAPRELAN is not recommended. Cholestyramine Clinical Impact: Concomitant administration of cholestyramine can delay the absorption of naproxen. Intervention: Concomitant administration of cholestyramine with NAPRELAN 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 NAPRELAN 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 NAPRELAN and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required. Drug/Laboratory Test Interactions 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 NAPRELAN 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 are determined. Drugs that Interfere with Hemostasis (e.g. warfarin, aspirin, SSRIs/SNRIs) : Monitor patients for bleeding who are concomitantly taking NAPRELAN with drugs that interfere with hemostasis. Concomitant use of NAPRELAN and analgesic doses of aspirin is not generally recommended ( 7 ) ACE Inhibitors, Angiotensin Receptor Blockers (ARB), or Beta-Blockers : Concomitant use with NAPRELAN may diminish the antihypertensive effect of these drugs. Monitor blood pressure ( 7 ) ACE Inhibitors and ARBs : Concomitant use with NAPRELAN 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 NAPRELAN can increase serum concentration and prolong half-life of digoxin. Monitor serum digoxin levels ( 7 )

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Naproxen has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of NAPRELAN, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Naproxen sodium is a potent inhibitor of prostaglandin synthesis in vitro . Naproxen sodium concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because naproxen sodium is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues. 12.2 Pharmacodynamics In a healthy volunteer study, 10 days of concomitant administration of naproxen 220 mg once-daily with low-dose immediate-release aspirin (81 mg) showed an interaction with the antiplatelet activity of aspirin as measured by % serum thromboxane B 2 inhibition at 24 hours following the day 10 dose [98.7% (aspirin alone) vs 93.1% (naproxen and aspirin)]. The interaction was observed even following discontinuation of naproxen on day 11 (while aspirin dose was continued) but normalized by day 13. In the same study, the interaction was greater when naproxen was administered 30 minutes prior to aspirin [98.7% vs 87.7%] and minimal when aspirin was administered 30 minutes prior to naproxen [98.7% vs 95.4%]. Following administration of naproxen 220 mg twice-daily with low-dose immediate-release aspirin (first naproxen dose given 30 minutes prior to aspirin), the interaction was minimal at 24 h following day 10 dose [98.7% vs 95.7%]. However, the interaction was more prominent after discontinuation of naproxen (washout) on day 11 [98.7% vs 84.3%] and did not normalize completely by day 13 [98.5% vs 90.7%]. [see Drug Interactions ( 7 )]. 12.3 Pharmacokinetics Although naproxen itself is well absorbed, the sodium salt form is more rapidly absorbed, resulting in higher peak plasma levels for a given dose. Approximately 30% of the total naproxen sodium dose in NAPRELAN Tablets is present in the dosage form as an immediate release component. The remaining naproxen sodium is coated as microparticles to provide sustained release properties. After oral administration, plasma levels of naproxen are detected within 30 minutes of dosing, with peak plasma levels occurring approximately 5 hours after dosing. The observed terminal elimination half-life of naproxen from both immediate release naproxen sodium and NAPRELAN Tablets is approximately 15 hours. Steady state levels of naproxen are achieved in 3 days and the degree of naproxen accumulation in the blood is consistent with this. Pharmacokinetic Parameters at Steady State Day 5 (Mean of 24 Subjects) Parameter (units) naproxen 500 mg Q12h/5 days (1000 mg) NAPRELAN 2 x 500 mg tablets (1000 mg) Q24h/5 days Mean SD Range Mean SD Range AUC 0-24 (mcgxh/mL) 1446 168 1167 - 1858 1448 145 1173 - 1774 C max (mcg/mL) 95 13 71 - 117 94 13 74 - 127 C avg (mcg/mL) 60 7 49 - 77 60 6 49 - 74 C min (mcg/mL) 36 9 13 - 51 33 7 23 - 48 T max (hrs) 3 1 1 - 4 5 2 2-10 Absorption Naproxen itself is rapidly and completely absorbed from the GI tract with an in vivo bioavailability of 95%. Based on the pharmacokinetic profile, the absorption phase of NAPRELAN Tablets occurs in the first 4 to 6 hours after administration. This coincides with disintegration of the tablet in the stomach, the transit of the sustained release microparticles through the small intestine and into the proximal large intestine. An in vivo imaging study has been performed in healthy volunteers that confirms rapid disintegration of the tablet matrix and dispersion of the microparticles. The absorption rate from the sustained release particulate component of NAPRELAN Tablets is slower than that for conventional naproxen sodium tablets. It is this prolongation of drug absorption processes that maintains plasma levels and allows for once daily dosing. Food Effects No significant food effects were observed when twenty-four subjects were given a single dose of NAPRELAN Tablets 500 mg either after an overnight fast or 30 minutes after a meal. In common with conventional naproxen and naproxen sodium formulations, food causes a slight decrease in the rate of naproxen absorption following NAPRELAN Tablets administration. Distribution Naproxen has a volume of distribution of 0.16 L/kg. At therapeutic levels, naproxen is greater than 99% albumin-bound. At doses of naproxen greater than 500 mg/day, there is a less than proportional increase in plasma levels due to an increase in clearance caused by saturation of plasma protein binding at higher doses. However the concentration of unbound naproxen continues to increase proportionally to dose. NAPRELAN Tablets exhibit similar dose proportional characteristics. Elimination Metabolism Naproxen is extensively metabolized to 6-0-desmethyl naproxen and both parent and metabolites do not induce metabolizing enzymes. Excretion The elimination half-life of NAPRELAN Tablets and conventional naproxen is approximately 15 hours. Steady state conditions are attained after 2 to 3 doses of NAPRELAN Tablets. Most of the drug is excreted in the urine, primarily as unchanged naproxen (less than 1%), 6-0-desmethyl naproxen (less than 1%) and their glucuronide or other conjugates (66 to 92%). A small amount (<5%) of the drug is excreted in the feces. The rate of excretion has been found to coincide closely with the rate of clearance from the plasma. In patients with renal failure, metabolites may accumulate. Specific Populations Pediatric: No pediatric studies have been performed with NAPRELAN Tablets, thus safety of NAPRELAN Tablets in pediatric populations has not been established. Hepatic Impairment: Chronic alcoholic liver disease and probably other diseases with decreased or abnormal plasma proteins (albumin) reduce the total plasma concentration of naproxen, but the plasma concentration of unbound naproxen is increased. 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. Renal Impairment: Naproxen pharmacokinetics have not been determined in subjects with renal insufficiency. Given that naproxen is metabolized and conjugates are primarily excreted by the kidneys, the potential exists for naproxen metabolites to accumulate in the presence of renal insufficiency. Elimination of naproxen is decreased in patients with severe renal impairment. Naproxen-containing products are not recommended for use in patients with moderate to severe and severe renal impairment (creatinine clearance <30mL/min) [ see Warnings and Precautions ( 5.6 ) ]. Drug Interaction Studies Aspirin: When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 1 for clinically significant drug interactions of NSAIDs with aspirin [ see Drug Interactions ( 7 ) ].

12.1 Mechanism of Action Naproxen has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of NAPRELAN, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Naproxen sodium is a potent inhibitor of prostaglandin synthesis in vitro . Naproxen sodium concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because naproxen sodium is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues.

12.2 Pharmacodynamics In a healthy volunteer study, 10 days of concomitant administration of naproxen 220 mg once-daily with low-dose immediate-release aspirin (81 mg) showed an interaction with the antiplatelet activity of aspirin as measured by % serum thromboxane B 2 inhibition at 24 hours following the day 10 dose [98.7% (aspirin alone) vs 93.1% (naproxen and aspirin)]. The interaction was observed even following discontinuation of naproxen on day 11 (while aspirin dose was continued) but normalized by day 13. In the same study, the interaction was greater when naproxen was administered 30 minutes prior to aspirin [98.7% vs 87.7%] and minimal when aspirin was administered 30 minutes prior to naproxen [98.7% vs 95.4%]. Following administration of naproxen 220 mg twice-daily with low-dose immediate-release aspirin (first naproxen dose given 30 minutes prior to aspirin), the interaction was minimal at 24 h following day 10 dose [98.7% vs 95.7%]. However, the interaction was more prominent after discontinuation of naproxen (washout) on day 11 [98.7% vs 84.3%] and did not normalize completely by day 13 [98.5% vs 90.7%]. [see Drug Interactions ( 7 )].

12.3 Pharmacokinetics Although naproxen itself is well absorbed, the sodium salt form is more rapidly absorbed, resulting in higher peak plasma levels for a given dose. Approximately 30% of the total naproxen sodium dose in NAPRELAN Tablets is present in the dosage form as an immediate release component. The remaining naproxen sodium is coated as microparticles to provide sustained release properties. After oral administration, plasma levels of naproxen are detected within 30 minutes of dosing, with peak plasma levels occurring approximately 5 hours after dosing. The observed terminal elimination half-life of naproxen from both immediate release naproxen sodium and NAPRELAN Tablets is approximately 15 hours. Steady state levels of naproxen are achieved in 3 days and the degree of naproxen accumulation in the blood is consistent with this. Pharmacokinetic Parameters at Steady State Day 5 (Mean of 24 Subjects) Parameter (units) naproxen 500 mg Q12h/5 days (1000 mg) NAPRELAN 2 x 500 mg tablets (1000 mg) Q24h/5 days Mean SD Range Mean SD Range AUC 0-24 (mcgxh/mL) 1446 168 1167 - 1858 1448 145 1173 - 1774 C max (mcg/mL) 95 13 71 - 117 94 13 74 - 127 C avg (mcg/mL) 60 7 49 - 77 60 6 49 - 74 C min (mcg/mL) 36 9 13 - 51 33 7 23 - 48 T max (hrs) 3 1 1 - 4 5 2 2-10 Absorption Naproxen itself is rapidly and completely absorbed from the GI tract with an in vivo bioavailability of 95%. Based on the pharmacokinetic profile, the absorption phase of NAPRELAN Tablets occurs in the first 4 to 6 hours after administration. This coincides with disintegration of the tablet in the stomach, the transit of the sustained release microparticles through the small intestine and into the proximal large intestine. An in vivo imaging study has been performed in healthy volunteers that confirms rapid disintegration of the tablet matrix and dispersion of the microparticles. The absorption rate from the sustained release particulate component of NAPRELAN Tablets is slower than that for conventional naproxen sodium tablets. It is this prolongation of drug absorption processes that maintains plasma levels and allows for once daily dosing. Food Effects No significant food effects were observed when twenty-four subjects were given a single dose of NAPRELAN Tablets 500 mg either after an overnight fast or 30 minutes after a meal. In common with conventional naproxen and naproxen sodium formulations, food causes a slight decrease in the rate of naproxen absorption following NAPRELAN Tablets administration. Distribution Naproxen has a volume of distribution of 0.16 L/kg. At therapeutic levels, naproxen is greater than 99% albumin-bound. At doses of naproxen greater than 500 mg/day, there is a less than proportional increase in plasma levels due to an increase in clearance caused by saturation of plasma protein binding at higher doses. However the concentration of unbound naproxen continues to increase proportionally to dose. NAPRELAN Tablets exhibit similar dose proportional characteristics. Elimination Metabolism Naproxen is extensively metabolized to 6-0-desmethyl naproxen and both parent and metabolites do not induce metabolizing enzymes. Excretion The elimination half-life of NAPRELAN Tablets and conventional naproxen is approximately 15 hours. Steady state conditions are attained after 2 to 3 doses of NAPRELAN Tablets. Most of the drug is excreted in the urine, primarily as unchanged naproxen (less than 1%), 6-0-desmethyl naproxen (less than 1%) and their glucuronide or other conjugates (66 to 92%). A small amount (<5%) of the drug is excreted in the feces. The rate of excretion has been found to coincide closely with the rate of clearance from the plasma. In patients with renal failure, metabolites may accumulate. Specific Populations Pediatric: No pediatric studies have been performed with NAPRELAN Tablets, thus safety of NAPRELAN Tablets in pediatric populations has not been established. Hepatic Impairment: Chronic alcoholic liver disease and probably other diseases with decreased or abnormal plasma proteins (albumin) reduce the total plasma concentration of naproxen, but the plasma concentration of unbound naproxen is increased. 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. Renal Impairment: Naproxen pharmacokinetics have not been determined in subjects with renal insufficiency. Given that naproxen is metabolized and conjugates are primarily excreted by the kidneys, the potential exists for naproxen metabolites to accumulate in the presence of renal insufficiency. Elimination of naproxen is decreased in patients with severe renal impairment. Naproxen-containing products are not recommended for use in patients with moderate to severe and severe renal impairment (creatinine clearance <30mL/min) [ see Warnings and Precautions ( 5.6 ) ]. Drug Interaction Studies Aspirin: When NSAIDs were administered with aspirin, the protein binding of NSAIDs were reduced, although the clearance of free NSAID was not altered. The clinical significance of this interaction is not known. See Table 1 for clinically significant drug interactions of NSAIDs with aspirin [ see Drug Interactions ( 7 ) ].

20230401

16

3 DOSAGE FORMS AND STRENGTHS NAPRELAN (naproxen sodium) Controlled-Release Tablets are available as follows: NAPRELAN 375: white, capsule-shaped tablet with “N” on one side and “375” on the reverse. Each tablet contains 412.5 mg naproxen sodium equivalent to 375 mg naproxen. NAPRELAN 500: white, capsule-shaped tablet with “N” on one side and “500” on the reverse. Each tablet contains 550 mg naproxen sodium equivalent to 500 mg naproxen. NAPRELAN 750: white, capsule-shaped tablet with “N” on one side and “750” on the reverse. Each tablet contains 825 mg naproxen sodium equivalent to 750 mg naproxen. NAPRELAN (naproxen sodium) Controlled-Release Tablets: 375 mg, 500 mg, and 750 mg ( 3 )

Naprelan Naproxen Sodium NAPROXEN SODIUM NAPROXEN AMMONIO METHACRYLATE COPOLYMER TYPE A AMMONIO METHACRYLATE COPOLYMER TYPE B CITRIC ACID MONOHYDRATE CROSPOVIDONE (120 .MU.M) MAGNESIUM STEARATE METHACRYLIC ACID - METHYL METHACRYLATE COPOLYMER (1:1) MICROCRYSTALLINE CELLULOSE POVIDONE, UNSPECIFIED TALC HYPROMELLOSE, UNSPECIFIED POLYETHYLENE GLYCOL, UNSPECIFIED TITANIUM DIOXIDE N;375 Naprelan Naproxen Sodium NAPROXEN SODIUM NAPROXEN AMMONIO METHACRYLATE COPOLYMER TYPE A AMMONIO METHACRYLATE COPOLYMER TYPE B CITRIC ACID MONOHYDRATE CROSPOVIDONE (120 .MU.M) MAGNESIUM STEARATE METHACRYLIC ACID - METHYL METHACRYLATE COPOLYMER (1:1) MICROCRYSTALLINE CELLULOSE POVIDONE, UNSPECIFIED TALC HYPROMELLOSE, UNSPECIFIED POLYETHYLENE GLYCOL, UNSPECIFIED TITANIUM DIOXIDE N;500 Naprelan Naproxen Sodium NAPROXEN SODIUM NAPROXEN AMMONIO METHACRYLATE COPOLYMER TYPE A AMMONIO METHACRYLATE COPOLYMER TYPE B CITRIC ACID MONOHYDRATE CROSPOVIDONE (120 .MU.M) MAGNESIUM STEARATE METHACRYLIC ACID - METHYL METHACRYLATE COPOLYMER (1:1) MICROCRYSTALLINE CELLULOSE POVIDONE, UNSPECIFIED TALC HYPROMELLOSE, UNSPECIFIED POLYETHYLENE GLYCOL, UNSPECIFIED TITANIUM DIOXIDE N;750 structure table 375mg 500mg 750mg

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis A two year study was performed in rats to evaluate the carcinogenic potential of naproxen at doses of 8 mg/kg/day, 16 mg/kg/day, and 24 mg/kg/day (0.05, 0.1, and 0.16 times the maximum recommended human daily dose of 1,500 mg/day based on a body surface area comparison). No evidence of tumorigenicity was found. Mutagenesis Studies to evaluate the mutagenic potential of Naprosyn Suspension have not been completed. Impairment of Fertility Studies to evaluate the impact of naproxen on male or female fertility have not been completed.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis A two year study was performed in rats to evaluate the carcinogenic potential of naproxen at doses of 8 mg/kg/day, 16 mg/kg/day, and 24 mg/kg/day (0.05, 0.1, and 0.16 times the maximum recommended human daily dose of 1,500 mg/day based on a body surface area comparison). No evidence of tumorigenicity was found. Mutagenesis Studies to evaluate the mutagenic potential of Naprosyn Suspension have not been completed. Impairment of Fertility Studies to evaluate the impact of naproxen on male or female fertility have not been completed.

NDA020353

Naprelan

Naproxen Sodium

52427-272

HUMAN PRESCRIPTION DRUG

ORAL

NDC 52427- 272 -01 Rx Only 375 mg NAPRELAN ® (naproxen sodium) CONTROLLED-RELEASE TABLETS Each tablet contains 412.5 mg naproxen sodium equivalent to 375 mg naproxen Dispense the accompanying Medication Guide to each patient. 100 Tablets Almatica ®

All trademarks are the property of their respective owners. Distributed by: Almatica Pharma, LLC Morristown, NJ 07960 USA PI272-09 Rev. 04/2023

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with NAPRELAN and periodically during the course of ongoing therapy. Cardiovascular Thrombotic Events Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [ see Warnings and Precautions ( 5.1 ) ]. Gastrointestinal Bleeding, Ulceration, and Perforation NAPRELAN, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [ see Warnings and Precautions ( 5.2 ) ]. Hepatotoxicity Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop NAPRELAN and seek immediate medical therapy [ see Warnings and Precautions ( 5.3 ) ]. Heart Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [ see Warnings and Precautions ( 5.5 ) ]. Anaphylactic Reactions Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [ see Contraindications ( 4 ) and Warnings and Precautions ( 5.7 ) ]. Serious Skin React ions, including DRESS NAPRELAN, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalization and even death. Advise patients to stop taking NAPRELAN immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [ see Warnings and Precautions ( 5.9, 5.10 ) ]. Female Fertility Advise females of reproductive potential who desire pregnancy that NSAIDs, including NAPRELAN, may be associated with a reversible delay in ovulation [ see Use in Specific Populations ( 8.3 ) ]. Fetal Toxicity Inform pregnant women to avoid use of NAPRELAN and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with NAPRELAN is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [ see Warnings and Precautions ( 5.11 ) and Use in Specific Populations ( 8.1 ) ]. Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of NAPRELAN with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [ see Warnings and Precautions ( 5.2 ) and Drug Interactions ( 7 ) ]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia. Use of NSAIDS and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with NAPRELAN until they talk to their healthcare provider [ see Drug Interactions ( 7 ) ].

Medication Guide for Nonsteroidal Anti-inflammatory Drugs (NSAIDs) What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)? NSAIDs can cause serious side effects, including: Increased risk of a heart attack or stroke that can lead to death. This risk may happen early in treatment and may increase: with increasing doses of NSAIDs with longer use of NSAIDs Avoid taking NSAIDs after a recent heart attack, unless your healthcare provider tells you to. You may have an increased risk of another heart attack if you take NSAIDs after a recent heart attack. Increased risk of bleeding, ulcers, and tears (perforation) of the esophagus (tube leading from the mouth to the stomach), stomach and intestines: anytime during use without warning symptoms that may cause death The risk of getting an ulcer or bleeding increases with: past history of stomach ulcers, or stomach or intestinal bleeding with use of NSAIDs taking medicines called “corticosteroids”, “anticoagulants”, “SSRIs”, or “SNRIs” increasing doses of NSAIDs longer use of NSAIDs smoking drinking alcohol older age poor health advanced liver disease bleeding problems NSAIDs should only be used: exactly as prescribed at the lowest dose possible for your treatment for the shortest time needed What are NSAIDs? NSAIDs are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as different types of arthritis, menstrual cramps, and other types of short-term pain. Who should not take NSAIDs? Do not take NSAIDs: • if you have had an asthma attack, hives, or other allergic reaction with aspirin or any other NSAIDs. • right before or after heart bypass surgery. Before taking NSAIDs, tell your healthcare provider about all of your medical conditions, including if you: have liver or kidney problems have high blood pressure have asthma are pregnant or plan to become pregnant. Taking NSAIDs at about 20 weeks of pregnancy or later may harm your unborn baby. If you need to take NSAIDs for more than 2 days when you are between 20 and 30 weeks of pregnancy, your healthcare provider may need to monitor the amount of fluid in your womb around your baby. You should not take NSAIDs after about 30 weeks of pregnancy. are breastfeeding or plan to breast feed. Tell your healthcare provider about all of the medicines you take, including prescription or over-the-counter medicines, vitamins or herbal supplements. NSAIDs and some other medicines can interact with each other and cause serious side effects. Do not start taking any new medicine without talking to your healthcare provider first. What are the possible side effects of NSAIDs? NSAIDs can cause serious side effects, including: See "What is the most important information I should know about medicines called Nonsteroidal Anti-inflammatory Drugs (NSAIDs)?" new or worse high blood pressure heart failure liver problems including liver failure kidney problems including kidney failure low red blood cells (anemia) life-threatening skin reactions life-threatening allergic reactions Other side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness. Get emergency help right away if you get any of the following symptoms: shortness of breath or trouble breathing chest pain weakness in one part or side of your body slurred speech swelling of the face or throat Stop taking your NSAID and call your healthcare provider right away if you get any of the following symptoms: nausea more tired or weaker than usual diarrhea itching your skin or eyes look yellow indigestion or stomach pain flu-like symptoms vomit blood there is blood in your bowel movement or it is black and sticky like tar unusual weight gain skin rash or blisters with fever swelling of the arms, legs, hands and feet If you take too much of your NSAID, call your healthcare provider or get medical help right away. These are not all the possible side effects of NSAIDs. For more information, ask your healthcare provider or pharmacist about NSAIDs. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. Other information about NSAIDs Aspirin is an NSAID but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. Some NSAIDs are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days. General information about the safe and effective use of NSAIDs Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use NSAIDs for a condition for which it was not prescribed. Do not give NSAIDs to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information about NSAIDs, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about NSAIDs that is written for health professionals. Distributed by: Almatica Pharma, LLC, Morristown, NJ 07960 USA For more information, call 1-877-447-7979 This Medication Guide has been approved by the U.S. Food and Drug Administration. PL272-09 Rev. 04/2023

14 CLINICAL STUDIES Rheumatoid Arthritis The use of NAPRELAN Tablets for the management of the signs and symptoms of rheumatoid arthritis was assessed in a 12 week double-blind, randomized, placebo, and active-controlled study in 348 patients. Two NAPRELAN 500 mg tablets (1,000 mg) once daily and naproxen 500 mg tablets twice daily (1,000 mg) were more effective than placebo. Clinical effectiveness was demonstrated at one week and continued for the duration of the study. Osteoarthritis The use of NAPRELAN Tablets for the management of the signs and symptoms of osteoarthritis of the knee was assessed in a 12 week double-blind, placebo, and active-controlled study in 347 patients. Two NAPRELAN 500 mg tablets (1,000 mg) once daily and naproxen 500 mg tablets twice daily (1,000 mg) were more effective than placebo. Clinical effectiveness was demonstrated at one week and continued for the duration of the study. Analgesia The onset of the analgesic effect of NAPRELAN Tablets was seen within 30 minutes in a pharmacokinetic/pharmacodynamic study of patients with pain following oral surgery. In controlled clinical trials, naproxen has been used in combination with gold, D-penicillamine, methotrexate, and corticosteroids. Its use in combination with salicylate is not recommended because there is evidence that aspirin increases the rate of excretion of naproxen and data are inadequate to demonstrate that naproxen and aspirin produce greater improvement over that achieved with aspirin alone. In addition, as with other NSAIDs the combination may result in higher frequency of adverse events than demonstrated for either product alone. Special Studies In a double-blind randomized, parallel group study, 19 subjects received either two NAPRELAN 500 mg tablets (1,000 mg) once daily or naproxen 500 mg tablets (1,000 mg) twice daily for 7 days. Mucosal biopsy scores and endoscopic scores were lower in the subjects who received NAPRELAN Tablets. In another double-blind, randomized, crossover study, 23 subjects received two NAPRELAN 500 mg tablets (1,000 mg) once daily, naproxen 500 mg tablets (1,000 mg) twice daily and aspirin 650 mg four times daily (2,600 mg) for 7 days each. There were significantly fewer duodenal erosions seen with NAPRELAN Tablets than with either naproxen or aspirin. There were significantly fewer gastric erosions with both NAPRELAN Tablets and naproxen than with aspirin. The clinical significance of these findings is unknown.

8.5 Geriatric Use 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 ) ]. Naproxen and its metabolites are known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, use caution in this patient population, and it may be useful to monitor renal function [ see Clinical Pharmacology ( 12.3 ) ].

8.2 Lactation Risk Summary The naproxen anion has been found in the milk of lactating women at a concentration of approximately 1% of that found in the plasma. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for NAPRELAN and any potential adverse effects on the breastfed infant from the NAPRELAN or from the underlying maternal condition.

8.4 Pediatric Use The safety and effectiveness of NAPRELAN in pediatric populations has not been established.

8.1 Pregnancy Risk Summary Use of NSAIDs, including NAPRELAN, 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 NAPRELAN use between about 20 and 30 weeks of gestation, and avoid NAPRELAN use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations, Data ). Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including NAPRELAN, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment 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 the general U.S. population, all clinically recognized pregnancies, regardless of drug exposure, have a background rate of 2-4% for major malformations, and 15-20% for pregnancy loss. In animal reproduction studies in rats, rabbit, 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 1,500 mg/day, respectively. 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. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including NAPRELAN, can cause premature closure of the fetal ductus arteriosus ( see Data ). Oligohydramnios/Neonatal Renal Impairment 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 NAPRELAN treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue NAPRELAN and follow up according to clinical practice ( see Data ). Labor or Delivery There are no studies on the effects of NAPRELAN during labor or delivery. In animal studies, NSAIDS, including naproxen sodium, inhibit prostaglandin synthesis, cause delayed parturition, increase incidence of dystocia 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 effect of drugs of this class on the human fetal cardiovascular system (closure of the ductus arteriosus), use during 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. Oligohydramnios/Neonatal Renal Impairment: 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. Animal data Reproduction studies have been performed in rats at 20 mg/kg/day (0.13 times the maximum recommended human daily dose of 1,500 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 sodium resulted in increased pre- and post-implantation loss.

8 USE IN SPECIFIC POPULATIONS Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal of NAPRELAN in women who have difficulties conceiving ( 8.3 ) 8.1 Pregnancy Risk Summary Use of NSAIDs, including NAPRELAN, 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 NAPRELAN use between about 20 and 30 weeks of gestation, and avoid NAPRELAN use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations, Data ). Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including NAPRELAN, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment 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 the general U.S. population, all clinically recognized pregnancies, regardless of drug exposure, have a background rate of 2-4% for major malformations, and 15-20% for pregnancy loss. In animal reproduction studies in rats, rabbit, 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 1,500 mg/day, respectively. 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. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including NAPRELAN, can cause premature closure of the fetal ductus arteriosus ( see Data ). Oligohydramnios/Neonatal Renal Impairment 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 NAPRELAN treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue NAPRELAN and follow up according to clinical practice ( see Data ). Labor or Delivery There are no studies on the effects of NAPRELAN during labor or delivery. In animal studies, NSAIDS, including naproxen sodium, inhibit prostaglandin synthesis, cause delayed parturition, increase incidence of dystocia 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 effect of drugs of this class on the human fetal cardiovascular system (closure of the ductus arteriosus), use during 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. Oligohydramnios/Neonatal Renal Impairment: 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. Animal data Reproduction studies have been performed in rats at 20 mg/kg/day (0.13 times the maximum recommended human daily dose of 1,500 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 sodium resulted in increased pre- and post-implantation loss. 8.2 Lactation Risk Summary The naproxen anion has been found in the milk of lactating women at a concentration of approximately 1% of that found in the plasma. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for NAPRELAN and any potential adverse effects on the breastfed infant from the NAPRELAN or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential Infertility Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including NAPRELAN, 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 NAPRELAN, in women who have difficulties conceiving or who are undergoing investigation of infertility. 8.4 Pediatric Use The safety and effectiveness of NAPRELAN in pediatric populations has not been established. 8.5 Geriatric Use 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 ) ]. Naproxen and its metabolites are known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, use caution in this patient population, and it may be useful to monitor renal function [ see Clinical Pharmacology ( 12.3 ) ].

16 HOW SUPPLIED/STORAGE AND HANDLING NAPRELAN (naproxen sodium) 375 mg, 500 mg, and 750 mg are controlled-release tablets supplied as: NAPRELAN 375: white, capsule-shaped tablet with “N” on one side and “375” on the reverse; in bottles of 100; NDC 52427-272-01. Each tablet contains 412.5 mg naproxen sodium equivalent to 375 mg naproxen. NAPRELAN 500: white, capsule-shaped tablet with “N” on one side and “500” on the reverse; in bottles of 75; NDC 52427-273-75. Each tablet contains 550 mg naproxen sodium equivalent to 500 mg naproxen. NAPRELAN 750: white, capsule-shaped tablet with “N” on one side and “750” on the reverse; in bottles of 30; NDC 52427-274-30. Each tablet contains 825 mg naproxen sodium equivalent to 750 mg naproxen. Storage Store at room temperature, 20°C to 25°C (68°F to 77°F), excursions permitted 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. PHARMACIST: Dispense in a well-closed container.

WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS Cardiovascular Thrombotic Events Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use [ see Warnings and Precautions ( 5.1 ) ]. NAPRELAN is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [ see Contraindications ( 4 ) and Warnings and Precautions ( 5.1 ) ]. Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs cause an increased risk of serious gastrointestinal (GI) 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 and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events [ see Warnings and Precautions ( 5.2 ) ]. WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS See full prescribing information for complete boxed warning. Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use ( 5.1 ) NAPRELAN ® is contraindicated in the setting of coronary artery bypass graft (CABG) surgery ( 4 , 5.1 ) NSAIDs cause an increased risk of serious gastrointestinal (GI) 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 and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events ( 5.2 )