Naproxen and esomeprazole magnesium

1 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 tablets 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 tablet is 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 )

2 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: • 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 do 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 )].

5 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 or Severe Skin Reactions: Discontinue naproxen and esomeprazole magnesium delayed-release tablets at first appearance of skin rash or other signs of hypersensitivity and consider further evaluation. ( 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 weeks 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 Wor…

4 CONTRAINDICATIONS Naproxen and esomeprazole magnesium delayed-release tablet is 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 Reaction ( 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 )

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 concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology ( 12.3 )]. • There are no adequate combination studies of a lower dose of esomeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel. 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 a…

8.1 Pregnancy Risk Summary Use of NSAIDs, including naproxen and esomeprazole magnesium delayed-release tablets, can cause premature closure of the fetal ductus arteriosus and fetal and renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of naproxen and esomeprazole magnesium delayed-release tablets use between about 20 weeks and 30 weeks of gestation and avoid naproxen and esomeprazole magnesium delayed-release tablets use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations, Data) . Premature Closure of the Fetal Ductus Arteriosus Use of NSAIDs, including naproxen and esomeprazole magnesium delayed-release tablets, 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. Naproxen and esomeprazole magnesium delayed-release tablets contain naproxen and esomeprazole magnesium. Esomeprazole is the S-isomer of omeprazole. Naproxen Data from observational studies regarding potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies, naproxen administered during organogenesis to rats and rabbits at doses less than the maximum recommended human daily dose of 1500 mg/day showed no evidence of harm to the fetus (see Data) . Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as naproxen resulted in increased pre-and post-implantation loss. 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. Esomeprazole There are no human data for esomeprazole. However, available epidemiologic data for omeprazole (esomeprazole is the S-isomer of omeprazole) fail to demonstrate an increased risk of major congenital malformations or other adverse pregnancy outcomes with first trimester omeprazole use (see Data) . In animal studies with administration of oral esomeprazole magnesium in rats, changes in bone morphology were observed in offspring of rats dosed through most of pregnancy and lactation at doses equal to or greater than approximately 34 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole. When maternal administration was confined to gestation only, there were no effects on bone physeal morphology in the offspring at any age [see Data] . The estimated background risks of major birth defects and miscarriage for the indicated population are 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 naproxen and esomeprazole magnesium delayed-release tablets, 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 naproxen and esomeprazole magnesium delayed-release tablets treatment is needed in pregnant women, consider monitoring…

8.3 Females and Males of Reproductive Potential Infertility Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including naproxen and esomeprazole magnesium delayed-release tablets, may delay or prevent rupture of ovarian follicles that may lead to reversible infertility in some women. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Published animal studies have shown that administration of prostaglandin synthesis inhibitors have the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Consider withdrawal of NSAIDs, including naproxen and esomeprazole magnesium delayed-release tablets, in women who have difficulties conceiving or who are undergoing investigation of infertility.

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 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 or Severe 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 (greater than 5%) are gastritis and diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Ajanta Pharma USA Inc. at 1-855-664-7744 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 was evaluated in clinical studies involving 2,317 patients (aged 27 years to 90 years) and ranging from 3 months to 12 months. Patients received either 500 mg/20 mg of naproxen and esomeprazole magnesium delayed-release tablets twice daily (n=1,157), 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 greater than 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 years to 69 years of age (83%). Approximately one quarter were on low-dose aspirin. Table 1: Adverse Reactions* in Study 1 and Study 2 (endoscopic studies) *reported in greater than 2% of patients and higher in the naproxen and esomeprazole magnesium delayed-release tablets group than control 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 rea…