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 )

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 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 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 greater than 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* in Study 3 and Study 4 *reported in greater than 2% of patients and higher in the naproxen and esomeprazole magnesium delayed-release tablets group than placebo 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 less than 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 less than 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, conjunctivitis Urogenital: cystitis, dysuria, oliguria/polyuria, proteinuria Clinical Trials Experience with Esomeprazole Magnesium Additional adverse reactions that were reported as possibly or probably related to esomeprazole magnesium with an incidence of less than 1% are listed below by body system: Body as a Whole: abdomen enlarged, allergic reaction, asthenia, back pain, chest pain, substernal chest pain, facial edema, hot flushes, fatigue, fever, flu-like disorder, generalized edema, malaise, pain, rigors Cardiovascular: flushing, hypertension, tachycardia Endocrine: goiter Gastrointestinal: dyspepsia, dysphagia, dysplasia GI, epigastric pain, eructation, esophageal disorder, gastroenteritis, GI hemorrhage, GI symptoms not otherwise specified, hiccup, melena, mouth disorder, pharynx disorder, rectal disorder, serum gastrin increased, tongue disorder, tongue edema, ulcerative stomatitis, vomiting Hearing: earache, tinnitus Hematologic: anemia, anemia hypochromic, cervical lymphadenopathy, epistaxis, leukocytosis, leukopenia, thrombocytopenia Hepatic : bilirubinemia, hepatic function abnormal, SGOT increased, SGPT increased Metabolic/Nutritional: glycosuria, hyperuricemia, hyponatremia, increased alkaline phosphatase, thirst, vitamin B12 deficiency, weight increase, weight decrease Musculoskeletal: arthralgia, arthritis aggravated, arthropathy, cramps, fibromyalgia syndrome, hernia, polymyalgia rheumatica Nervous System/Psychiatric: anorexia, apathy, appetite increased, confusion, depression aggravated, hypertonia, nervousness, hypoesthesia, impotence, insomnia, migraine, migraine aggravated, paresthesia, sleep disorder, somnolence, tremor, vertigo, visual field defect Reproductive: dysmenorrhea, menstrual disorder, vaginitis Respiratory: asthma aggravated, coughing, dyspnea, larynx edema, pharyngitis, rhinitis, sinusitis Skin and Appendages: acne, angioedema, dermatitis, pruritus, pruritus ani, rash, rash erythematous, rash maculo-papular, skin inflammation, sweating increased, urticaria Special Senses: otitis media, parosmia, taste loss Urogenital: abnormal urine, albuminuria, cystitis, dysuria, fungal infection, hematuria, micturition frequency, moniliasis, genital moniliasis, polyuria Visual: conjunctivitis, vision abnormal The following potentially clinically significant laboratory changes in clinical trials, irrespective of relationship to esomeprazole magnesium, were reported in less than or equal to 1% of patients: increased creatinine, uric acid, total bilirubin, alkaline phosphatase, ALT, AST, hemoglobin, white blood cell count, platelets, serum gastrin, potassium, sodium, thyroxine and thyroid stimulating hormone.

Decreases were seen in hemoglobin, white blood cell count, platelets, potassium, sodium, and thyroxine.

Endoscopic findings that were reported as adverse reactions include: duodenitis, esophagitis, esophageal stricture, esophageal ulceration, esophageal varices, gastric ulcer, hernia, benign polyps or nodules, Barrett’s esophagus, and mucosal discoloration.

6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of naproxen and esomeprazole magnesium delayed-release tablets.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Naproxen and Esomeprazole Magnesium Delayed-Release Tablets Body as a Whole: gait disturbance Gastrointestinal: abdominal distension, abdominal pain, gastroesophageal reflux, hematochezia Injury, Poisoning and Procedural Complications: contusion, fall Musculoskeletal and Connective Tissue: joint swelling, muscle spasms Urogenital: renal tubular necrosis Naproxen Body as a Whole: angioneurotic edema, menstrual disorders Cardiovascular: congestive heart failure, vasculitis, pulmonary edema Gastrointestinal: inflammation, bleeding (sometimes fatal, particularly in the elderly), ulceration, and obstruction of the upper or lower gastrointestinal tract, esophagitis, stomatitis, hematemesis, colitis, exacerbation of inflammatory bowel disease (ulcerative colitis, Crohn’s disease) Hepatobiliary: hepatitis (some cases have been fatal) Hemic and Lymphatic: eosinophilia, hemolytic anemia, aplastic anemia Metabolic and Nutritional: hyperglycemia, hypoglycemia Nervous System: depression, dream abnormalities, insomnia, malaise, myalgia, muscle weakness, aseptic meningitis, cognitive dysfunction, convulsions Respiratory: eosinophilic pneumonitis Dermatologic: alopecia, urticaria, toxic epidermal necrolysis, erythema multiforme, erythema nodosum, fixed drug eruption, lichen planus, pustular reaction, systemic lupus erythematoses, bullous reactions, including exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), fixed drug eruption (FDE), photosensitive dermatitis, photosensitivity reactions, including rare cases resembling porphyria cutanea tarda (pseudoporphyria) or epidermolysis bullosa.

If skin fragility, blistering or other symptoms suggestive of pseudoporphyria occur, treatment should be discontinued and the patient monitored.

Special Senses: hearing impairment, corneal opacity, papillitis, retrobulbar optic neuritis, papilledema Urogenital: glomerular nephritis, hematuria, hyperkalemia, interstitial nephritis, nephrotic syndrome, renal disease, renal failure, renal papillary necrosis, raised serum creatinine Reproduction (female) : infertility Esomeprazole Magnesium Blood and Lymphatic: agranulocytosis Eye: blurred vision Gastrointestinal: pancreatitis, microscopic colitis, fundic gland polyps Hepatobiliary: hepatic failure, hepatitis with or without jaundice Immune System: anaphylactic reaction/shock, systemic lupus erythematosus Infections and Infestations: GI candidiasis, Clostridium difficile associated diarrhea Metabolism and Nutritional Disorders: hypomagnesemia, hypocalcemia, hypokalemia [see Warnings and Precautions ( 5.24 )] , hyponatremia Musculoskeletal and Connective Tissue: muscular weakness, myalgia, bone fracture Nervous System: hepatic encephalopathy Psychiatric: aggression, agitation, hallucination Renal and Urinary: interstitial nephritis Reproductive System and Breast: gynecomastia, erectile dysfunction Respiratory, Thoracic, and Mediastinal: bronchospasm Skin and Subcutaneous Tissue: alopecia, erythema multiforme, photosensitivity, SJS, TEN (some fatal), DRESS, AGEP, cutaneous lupus erythematosus