Naproxen and Esomeprazole Magnesium

INDICATIONS AND USAGE Naproxen and esomeprazole magnesium delayed-release tablets, a combination of naproxen and esomeprazole magnesium, is indicated in adult and adolescent patients 12 years of age and older weighing at least 38 kg, requiring naproxen for symptomatic relief of arthritis and esomeprazole magnesium to decrease the risk for developing naproxen-associated gastric ulcers. The naproxen component of naproxen and esomeprazole magnesium delayed-release tablet is indicated for relief of signs and symptoms of: • osteoarthritis, rheumatoid arthritis and ankylosing spondylitis in adults. • juvenile idiopathic arthritis (JIA) in adolescent patients. The esomeprazole magnesium component of naproxen and esomeprazole magnesium delayed-release tablet is indicated to decrease the risk of developing naproxen-associated gastric ulcers. Limitations of Use : • Do not substitute naproxen and esomeprazole magnesium delayed-release tablet with the single-ingredient products of naproxen and esomeprazole magnesium. • Naproxen and esomeprazole magnesium delayed-release tablets are not recommended for initial treatment of acute pain because the absorption of naproxen is delayed compared to absorption from other naproxen-containing products. • Controlled studies do not extend beyond 6 months [see Use in Specific Populations ( 8.4 ), Clinical Studies ( 14 )] . Naproxen and esomeprazole magnesium delayed-release tablets are a combination of naproxen, a non-steroidal anti-inflammatory drug (NSAID), and esomeprazole magnesium, a proton pump inhibitor (PPI) indicated in adult and adolescent patients 12 years of age and older weighing at least 38 kg, requiring naproxen for symptomatic relief of arthritis and esomeprazole magnesium to decrease the risk of developing naproxen-‑associated gastric ulcers. The naproxen component of naproxen and esomeprazole magnesium delayed-release tablet is indicated for relief of signs and symptoms of: • osteoarthritis, rheumatoid arthritis and ankylosing spondylitis in adults. • juvenile idiopathic arthritis (JIA) in adolescent patients. The esomeprazole magnesium component of naproxen and esomeprazole magnesium delayed-release tablet is indicated to decrease the risk of developing naproxen-associated gastric ulcers. ( 1 ) Limitations of Use: • Do not substitute naproxen and esomeprazole magnesium delayed-release tablets with the single-ingredient products of naproxen and esomeprazole magnesium. ( 1 ) • Naproxen and esomeprazole magnesium delayed-release tablets are not recommended for initial treatment of acute pain because the absorption of naproxen is delayed compared to absorption from other naproxen-containing products. ( 1 ) • Controlled studies do not extend beyond 6 months. ( 1 )

DOSAGE AND ADMINISTRATION Administration • Use the lowest naproxen dose for the shortest duration consistent with individual patient treatment goals. ( 2.1 , 5.1 ). • If a total daily dose of less than 40 mg esomeprazole is more appropriate, a different treatment should be considered. ( 2.1 ) • Swallow naproxen and Esomeprazole magnesium delayed-release tablets whole with liquid at least 30 minutes before meals. ( 2.1 ) Recommended Dosage ( 2.2 ) Adolescents 12 years of age and older weighing 38 kg to less than 50 kg : One naproxen and esomeprazole magnesium delayed-release tablet twice daily of 375 mg naproxen/20 mg of esomeprazole Adults and adolescents 12 years of age and older greater than 50 kg : One naproxen and esomeprazole magnesium delayed-release tablet twice daily of either: • 375 mg naproxen/20 mg of esomeprazole; or • 500 mg of naproxen/20 mg of esomeprazole Renal or Hepatic Impairment ( 2.3 ) • Avoid in moderate/severe renal impairment or severe hepatic impairment. • Consider dose reduction in mild/moderate hepatic impairment. 2.1 Important Administration Instructions • Use the lowest naproxen dose for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5.1) ] . • Carefully consider the potential benefits and risks of naproxen and esomeprazole magnesium delayed-release tablets and other treatment options before deciding to use naproxen and esomeprazole magnesium delayed-release tablets. • Naproxen and esomeprazole magnesium delayed-release tablets does not allow for administration of a lower daily dose of esomeprazole magnesium. If a total daily dose of less than 40 mg esomeprazole is more appropriate, a different treatment should be considered. • Swallow naproxen and esomeprazole magnesium delayed-release tablets whole with liquid. Do not split, chew, crush or dissolve the tablet. Take naproxen and esomeprazole magnesium delayed-release tablets at least 30 minutes before meals. • Patients should be instructed that if a dose is missed, it should be taken as soon as possible. However, if the next scheduled dose is due, the patient should not take the missed dose, and should be instructed to take the next dose on time. Patients should be instructed not to take 2 doses at one time to make up for a missed dose. • Antacids may be used while taking naproxen and esomeprazole magnesium delayed-release tablets. 2.2 Recommended Dosage The recommended dosage of naproxen and esomeprazole magnesium delayed-release tablets by indication is shown in the table: Indication Patient Population Recommended Dosage Rheumatoid Arthritis, Osteoarthritis, and Ankylosing Spondylitis Adults One naproxen and esomeprazole magnesium delayed-release tablet twice daily of either: 375 mg naproxen/20 mg of esomeprazole; or 500 mg naproxen/20 mg of esomeprazole Juvenile Idiopathic Arthritis in Adolescent Patients 12 Years of Age and Older and Weighing at Least 38 kg Greater than 50 kg 38 kg to less than 50 kg One naproxen and esomeprazole magnesium delayed-release tablet twice daily of: 375 mg naproxen/20 mg of esomeprazole 2.3 Use in Renal Impairment or Hepatic Impairment Renal Impairment Naproxen-containing products are not recommended for use in patients with moderate to severe or severe renal impairment (creatinine clearance less than 30 mL/min) [see Warnings and Precautions (5.6) , Use in Specific Populations (8.7) ] . Hepatic Impairment Monitor patients with mild to moderate hepatic impairment closely and consider a possible dose reduction based on the naproxen component of naproxen and esomeprazole magnesium delayed-release tablets. Naproxen and esomeprazole magnesium delayed-release tablets should be avoided in patients with severe hepatic impairment [see Warnings and Precautions (5.3) , Use in Specific Populations (8.6) ].

WARNINGS AND PRECAUTIONS Hepatotoxicity : Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop. ( 5.3 ) Hypertension : Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure. ( 5.4 , 7 ) Heart Failure and Edema : Avoid use of naproxen and esomeprazole magnesium delayed-release tablets in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure. ( 5.5 ) Renal Toxicity : Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of naproxen and esomeprazole magnesium delayed-release tablets in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function. ( 5.6 ) Anaphylactic Reactions : Seek emergency help if an anaphylactic reaction occurs. ( 5.7 ) Exacerbation of Asthma Related to Aspirin Sensitivity : Naproxen and esomeprazole magnesium delayed-release tablets are contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity). ( 5.8 ) Serious Skin Reactions : Discontinue naproxen and esomeprazole magnesium delayed-release tablets at first appearance of skin rash or other signs of hypersensitivity. ( 5.9 ) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue and evaluate clinically ( 5.10 ) Fetal Toxicity : Limit use of NSAIDs, including naproxen and esomeprazole magnesium delayed-release tablets, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal renal dysfunction and premature closure of the fetal ductus arteriosus ( 5.11 , 8.1 ) Hematologic Toxicity : Monitor hemoglobin or hematocrit in patients with any signs of symptoms of anemia. ( 5.12 , 7 ) Masking of Inflammation and Fever : Potential for diminished utility of diagnostic signs in detecting infections. ( 5.13 ) Laboratory Monitoring : Obtain CBC and chemistry profile periodically during treatment. Monitor hemoglobin periodically in patients on long- term treatment who have an initial value of 10 g or less. ( 5.14 ) Active Bleeding : Withdraw treatment in patients who experience active and clinically significant bleeding. ( 5.15 ) Concomitant NSAID Use : Do not use naproxen and esomeprazole magnesium delayed-release tablets with other naproxen -containing products or other non-aspirin NSAIDs. ( 5.16 ) Gastric Malignancy : In adults, symptomatic response to esomeprazole does not preclude the presence of gastric malignancy. Consider additional follow-up and diagnostic testing. ( 5.17 ) Acute Tubulointerstitial Nephritis : Discontinue treatment and evaluate patients. ( 5.18 ) Clostridium difficile -Associated Diarrhea : PPI therapy may be associated with increased risk of Clostridium difficile associated diarrhea. ( 5.19 ) Bone Fracture : Long-term and multiple daily dose PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist or spine. ( 5.20 ) Cutaneous and Systemic Lupus Erythematosus : Mostly cutaneous, new onset or exacerbation of existing disease; discontinue naproxen and esomeprazole magnesium delayed-release tablets and refer to specialist for evaluation. ( 5.21 ) Interaction with Clopidogrel : Avoid concomitant use. ( 5.22 , 7 ) Cyanocobalamin (Vitamin B-12) Deficiency : Daily long-term use (e.g., longer than 3 years) may lead to malabsorption or a deficiency of cyanocobalamin. ( 5.23 ) Hypomagnesemia and Mineral Metabolism : Reported rarely with prolonged treatment with PPIs. ( 5.24 ) Interaction with St. John’s Wort or Rifampin : Avoid concomitant use. ( 5.25 , 7 ) Interactions with Diagnostic Investigations for Neuroendocrine Tumors : Increases in intragastric pH may result in hypergastrinemia, enterochromaffin-like cell hyperplasia, and increased Chromogranin A levels which may interfere with diagnostic investigations for neuroendocrine tumors. ( 5.26 ) Interaction with Methotrexate : Concomitant use with PPIs may elevate and/or prolong serum concentrations of methotrexate and/or its metabolite, possibly leading to toxicity. ( 5.27 , 7 ) Fundic Gland Polyps : Risk increases with long-term PPI use, especially beyond one year. Use the shortest duration of therapy. ( 5.28 ) 5.1 Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI), and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDS. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as naproxen, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2) ] . Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see Contraindications (4) ] . Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100-person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years after follow-up. Avoid the use of naproxen and esomeprazole magnesium delayed-release tablets in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If naproxen and esomeprazole magnesium delayed-release tablets are used in patients with a recent MI, monitor patients for signs of cardiac ischemia. 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including naproxen, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or w

CONTRAINDICATIONS Naproxen and esomeprazole magnesium delayed-release tablets are contraindicated in the following patients: • Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to naproxen, esomeprazole magnesium, substituted benzimidazoles, or to any components of the drug product, including omeprazole. Hypersensitivity reactions to esomeprazole may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute tubulointerstitial nephritis, and urticaria [see Warnings and Precautions ( 5.7 , 5.8 , 5.9 , 5.18 ), Adverse Reactions ( 6.2 )]. • History of asthma, urticaria, or 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) ]. • Proton pump inhibitors (PPIs), including esomeprazole magnesium, are contraindicated in patients receiving rilpivirine-containing products [see Drug Interactions ( 7 ) ]. • Known hypersensitivity to naproxen, esomeprazole magnesium, substituted benzimidazoles, or to any components of the drug product including omeprazole. (4 ) • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. ( 4 ) • In the setting of coronary artery bypass graft (CABG) surgery. ( 4 ) • In patients receiving rilpivirine-containing products. ( 4 , 7 )

DRUG INTERACTIONS See Table 3 and Table 4 for clinically significant drug interactions and interactions with diagnostics with naproxen and esomeprazole magnesium. Table 3: Clinically Significant Drug Interactions with Naproxen and Esomeprazole Magnesium – Affecting Drugs Co-Administered with Naproxen and Esomeprazole magnesium delayed-release tablets and Interactions with Diagnostics Clinical Impact: Naproxen • Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants have increased the 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. Esomeprazole Magnesium • Increased INR and prothrombin time in patients treated with PPIs, including esomeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. • Concomitant use of esomeprazole 40 mg resulted in reduced plasma Intervention: Monitor patients with concomitant use of naproxen and esomeprazole magnesium delayed-release tablets 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 (5.14) ]. Clopidogrel: Avoid concomitant use of clopidogrel with naproxen and esomeprazole magnesium delayed-release tablets. Consider use of alternative anti-platelet therapy [see Warnings and Precautions (5.22) ]. Aspirin Clinical Impact: A pharmacodynamics (PD) study has demonstrated an interaction in which lower dose naproxen (220mg/day or 220mg twice daily) interfered with the antiplatelet effect of low-dose immediate-release aspirin, with the interaction most marked during the washout period of naproxen [see Clinical Pharmacology (12.2.) ]. There is reason to expect that the interaction would be present with prescription doses of naproxen or with enteric-coated low-dose aspirin; however, the peak interference with aspirin function may be later than observed in the PD study due to the longer washout period. Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2) ]. Intervention: Because there may be an increased risk of cardiovascular events following discontinuation of naproxen due to the interference with the antiplatelet effect of aspirin during the washout period, for patients taking low-dose aspirin for cardioprotection who require intermittent analgesics, consider use of an NSAID that does not interfere with the antiplatelet effect of aspirin, or non-NSAID analgesics where appropriate. Concomitant use of naproxen and esomeprazole magnesium delayed-release tablets and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.12) ] . Naproxen and esomeprazole magnesium delayed-release tablets are 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 and esomeprazole magnesium delayed-release tablets and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • During concomitant use of naproxen and esomeprazole magnesium delayed-release tablets 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) ] . 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 and esomeprazole magnesium delayed-release tablets 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) ] . Antiretrovirals Clinical Impact: The effect of esomeprazole magnesium on antiretroviral drugs is variable. The clinical importance and mechanisms behind these interactions are not always known. • Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir, and nelfinavir) when used concomitantly with esomeprazole magnesium may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology (12.3) ]. • Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with esomeprazole magnesium may increase toxicity [see Clinical Pharmacology (12.3) ] . • There are other antiretroviral drugs which do not result in clinically relevant interactions with esomeprazole magnesium. Intervention: Rilpivirine-containing products : Concomitant use with naproxen and esomeprazole magnesium delayed-release tablets is contraindicated [see Contraindications (4) ] . A tazanavir: See prescribing information for atazanavir for dosing information. N elfinavir: Avoid concomitant use with naproxen and esomeprazole magnesium delayed-release tablets. S aquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities. Other antiretrovirals : See prescribing information of specific drugs. Cilostazol Clinical Impact: Increased exposure of cilostazol and one of its active metabolites (3,4-dihydro-cilostazol) when coadministered with omeprazole magnesium, the racemate of esomeprazole [see Clinical Pharmacology (12.3) ]. Intervention: Consider reducing the dose of cilostazol to 50 mg twice daily. Digoxin Clinical Impact: Naproxen • The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Esomeprazole Magnesium • Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3) ] . Intervention: Monitor digoxin concentrations during concomitant use of naproxen and esomeprazole magnesium delayed-release tablets. Dose adjustment of digoxin may be needed to maintain therapeutic drug concentrations. Lithium Clinical Impact: NSAIDs have produced elevations of 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 and esomeprazole magnesium delayed-release tablets and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Naproxen • Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfun

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 Perforations [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) ] Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions (5.10) ] Fetal Toxicity [see Warnings and Precautions (5.11) ] Hematologic Toxicity [see Warnings and Precautions (5.12) ] Active Bleeding [see Warnings and Precautions (5.15) ] Acute Tubulointerstitial Nephritis [see Warnings and Precautions (5.18) ] Clostridium difficile- Associated Diarrhea [see Warnings and Precautions (5.19) ] Bone Fracture [see Warnings and Precautions (5.20) ] Cutaneous and Systemic Lupus Erythematosus [see Warnings and Precautions (5.21) ] Cyanocobalamin (Vitamin B-12) Deficiency [see Warnings and Precautions (5.23) ] Hypomagnesemia and Mineral Metabolism [see Warnings and Precautions (5.24) ] Fundic Gland Polyps [see Warnings and Precautions (5.28) ] Most common adverse reactions in clinical trials (>5%) are gastritis and diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact ScieGen Pharmaceuticals Inc. at 1-855-724-3436 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Clinical Trials Experience with naproxen and esomeprazole magnesium delayed release tablets 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. The adverse reactions reported below are specific to the clinical trials with naproxen and esomeprazole magnesium delayed-release tablets. The safety of naproxen and esomeprazole magnesium delayed-release tablets were evaluated in clinical studies involving 2317 patients (aged 27 to 90 years) and ranging from 3 to 12 months. Patients received either 500 mg/20 mg of naproxen and esomeprazole magnesium delayed-release tablets twice daily (n=1157), 500 mg of enteric-coated naproxen twice daily (n=426), or placebo (n=246). The average number of naproxen and esomeprazole magnesium delayed-release tablets doses taken over 12 months was 69 6 ±44. The table below lists all adverse reactions, regardless of causality, occurring in > 2% of patients receiving naproxen and esomeprazole magnesium delayed-release tablets and higher in the naproxen and esomeprazole magnesium delayed-release tablets group than control from two clinical studies (Study 1 and Study 2). Both of these studies were randomized, multi-center, double-blind, parallel studies. The majority of patients were female (67%), white (86%). The majority of patients were 50 to 69 years of age (83%). Approximately one quarter were on low-dose aspirin. Table 1: Adverse Reactions reported in > 2% of patients and higher in the naproxen and esomeprazole magnesium delayed-release tablets group than control in Study 1 and Study 2 (endoscopic studies) Preferred term Naproxen and esomeprazole magnesium delayed-release tablets 500 mg/20 mg twice daily (n=428) % EC-Naproxen 500 mg twice daily (n=426) % Gastritis 17 14 Diarrhea 6 5 Upper respiratory tract infection 5 4 Flatulence 4 3 Headache 3 1 Urinary tract infection 2 1 Dysgeusia 2 1 In Study 1 and Study 2, patients taking naproxen and esomeprazole magnesium delayed-release tablets had fewer premature discontinuations due to adverse reactions compared to patients taking enteric-coated naproxen alone (7.9% vs. 12.5% respectively). The most common reasons for discontinuations due to adverse events in the naproxen and esomeprazole magnesium delayed-release tablets treatment group were upper abdominal pain (1.2%, n=5), duodenal ulcer (0.7%, n=3) and erosive gastritis (0.7%, n=3). Among patients receiving enteric-coated naproxen, the most common reasons for discontinuations due to adverse events were duodenal ulcer 5.4% (n=23), dyspepsia 2.8% (n=12) and upper abdominal pain 1.2% (n=5). The proportion of patients discontinuing treatment due to any upper gastrointestinal adverse events (including duodenal ulcers) in patients treated with naproxen and esomeprazole magnesium delayed-release tablets was 4% compared to 12% for patients taking enteric-coated naproxen. The table below lists all adverse reactions, regardless of causality, occurring in > 2% of patients and higher in the naproxen and esomeprazole magnesium delayed-release tablets group than placebo from 2 clinical studies conducted in patients with osteoarthritis of the knee (Study 3 and Study 4). Table 2: Adverse Reactions reported in > 2% of patients and higher in the naproxen and esomeprazole magnesium delayed-release tablets group than placebo in Study 3 and Study 4 Preferred term Naproxen and Esomeprazole magnesium delayed-release tablets 500 mg/20 mg twice daily (n=490) % Placebo (n=246) % Diarrhea 6 4 Abdominal Pain Upper 4 3 Constipation 4 1 Dizziness 3 2 Peripheral edema 3 1 The percentage of subjects who withdrew from the naproxen and esomeprazole magnesium delayed-release tablets treatment group in these studies due to treatment-emergent adverse events was 7%. There were no preferred terms in which more than 1% of subjects withdrew from any treatment group. The long-term safety of naproxen and esomeprazole magnesium delayed-release tablets was evaluated in an open-label clinical trial of 239 patients, of which 135 patients received 500 mg/20 mg of naproxen and esomeprazole magnesium delayed-release tablets for 12 months. There were no differences in frequency or types of adverse reactions seen in the long-term safety study compared to shorter-term treatment in the randomized controlled studies. Clinical Trials Experience with Naproxen and Other NSAIDs In patients taking naproxen in clinical trials, the most frequent reported adverse experiences in approximately 1% to 10% of patients are: Gastrointestinal: heartburn, nausea, dyspepsia, stomatitis Central Nervous System: drowsiness, lightheadedness, vertigo Dermatologic: pruritus, skin eruptions, ecchymoses, sweating, purpura Special Senses: tinnitus, visual disturbances, hearing disturbances Cardiovascular: palpitations General: dyspnea, thirst In patients taking NSAIDs, the following adverse experiences have also been reported in approximately 1% to 10% of patients. Gastrointestinal: gross bleeding/perforation, GI ulcers (gastric/duodenal), vomiting General: abnormal renal function, anemia, elevated liver enzymes, increased bleeding time, rashes The following are additional adverse experiences reported in <1% of patients taking naproxen during clinical trials. Gastrointestinal: pancreatitis Hepatobiliary: jaundice Hemic and Lymphatic: melena, thrombocytopenia, agranulocytosis Nervous System: inability to concentrate Dermatologic: skin rashes In patients taking NSAIDs, the following adverse experiences have also been reported in < 1% of patients. Body as a Whole: fever, infection, sepsis, anaphylactic reactions, appetite changes, death Cardiovascular: hypertension, tachycardia, syncope, arrhythmia, hypotension, myocardial infarction Gastrointestinal: dry mouth, glossitis, eructation Hepatobiliary: hepatitis, liver failure Hemic and Lymphatic: rectal bleeding, lymphadenopathy, pancytopenia Metabolic and Nutritional: weight changes Nervous System: anxiety, asthenia, confusion, nervousness, paresthesia, somnolence, tremor, coma, hallucinations Respiratory: asthma, respiratory depression, pneumonia Dermatologic: exfoliative dermatitis Special Senses: blurred vision,

Mechanism of Action Naproxen and esomeprazole magnesium delayed-release tablets consist of an immediate-release esomeprazole magnesium layer and an enteric-coated naproxen core. As a result, esomeprazole is released first in the stomach, prior to the dissolution of naproxen in the small intestine. The enteric coating prevents naproxen release at pH levels below 5.5. The mechanism of action of the naproxen anion, like that of other NSAIDs, is not completely understood but inhibition of cyclooxygenase (COX-1 and COX-2). Naproxen and esomeprazole magnesium delayed-release tablets have analgesic, anti-inflammatory, and antipyretic properties contributed by the naproxen component. Naproxen is a potent inhibitor of prostaglandin synthesis in vitro . Naproxen 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 is an inhibitor of prostaglandin synthesis, its mode of action may be due to an increase of prostaglandins in peripheral tissues. Esomeprazole is a proton pump inhibitor that suppresses gastric acid secretion by specific inhibition of the H + /K + -ATPase in the gastric parietal cell. Esomeprazole is protonated and converted in the acidic compartment of the parietal cell forming the active inhibitor, the achiral sulphenamide. By acting specifically on the proton pump, esomeprazole blocks the final step in acid production, thus reducing gastric acidity. This effect is dose-related up to a daily dose of 20 mg to 40 mg and leads to inhibition of gastric acid secretion.