Naproxen And Esomeprazole Magnesium

Description

11 DESCRIPTION The active ingredients of naproxen and esomeprazole magnesium delayed-release tablets are naproxen, USP which is an NSAID and esomeprazole magnesium, USP which is a Proton Pump Inhibitor (PPI). Naproxen and esomeprazole magnesium delayed-release tablets are combination of a nonsteroidal anti-inflammatory drug and a PPI available as an oval, yellow, multi-layer, delayed-release tablet combining an enteric-coated naproxen core and an immediate-release esomeprazole magnesium layer surrounding the core. Each strength contains either 375 mg of naproxen, USP and 20 mg of esomeprazole (equivalent to 21.75 mg esomeprazole magnesium dihydrate) or 500 mg of naproxen and 20 mg of esomeprazole (equivalent to 21.75 mg esomeprazole magnesium dihydrate) for oral administration. The inactive ingredients are microcrystalline cellulose, croscarmellose sodium, povidone, colloidal silicon dioxide, magnesium stearate, methacrylic acid and ethyl acrylate copolymer, talc, triethy citrate, hypromellose, macrogol, sodium lauryl sulfate, magnesium oxide, polyethylene glycol, ferric oxide yellow. The imprinting ink contains shellac glaze, black iron oxide, propylene glycol, ammonium hydroxide. The chemical name for naproxen, USP is (S)-2-(6-Methoxy-naphth-2-yl) propionic acid. Naproxen, USP has the following structure: Naproxen, USP has a molecular weight of 230.26 and a molecular formula of C 14 H 14 O 3 . Naproxen, USP is an odorless, white to off-white crystalline powder. It is practically insoluble in water and soluble in ethanol and methanol. The octanol/water partition coefficient of naproxen is 3.18. The chemical name for esomeprazole is Magnesium bis [5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulphinyl]-1Hbenzimidazol-1- ide]dihydrate. Esomeprazole is the S-isomer of omeprazole, which is a mixture of the S-and R-isomers. Its molecular formula is C 34 H 36 N 6 O 6 S 2 Mg.2H 2 O with molecular weight of 749.15 as a dihydrate and 713.15 on an anhydrous...

What Is Naproxen And Esomeprazole Magnesium Used For?

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 )

Dosage and Administration

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 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 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...

Side Effects (Adverse Reactions)

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...

Drug Interactions

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...

Contraindications

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 )

Pregnancy and Breastfeeding

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...

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.

Overdosage

10 OVERDOSAGE There is no clinical data on overdosage with naproxen and esomeprazole magnesium delayed-release tablets. Overdosage of naproxen : 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. The oral LD50 of the drug is 500 mg/kg in rats, 1200 mg/kg in mice, 4000 mg/kg in hamsters and greater than 1000 mg/kg in dogs. In animals 0.5 g/kg of activated charcoal was effective in reducing plasma levels of naproxen. 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. Overdosage of esomeprazole: A single oral dose of esomeprazole at 510 mg/kg (about 124 times the human dose on a body surface area basis) was lethal to rats. The major signs of acute toxicity were reduced motor activity, changes in respiratory frequency, tremor, ataxia, and intermittent clonic convulsions. The symptoms described in connection with deliberate esomeprazole overdose (limited experience of doses in excess of 240...

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING Naproxen and esomeprazole magnesium delayed-release tablets 500 mg/20 mg are yellow colored, oval shaped, biconvex film-coated tablets with NE 500 imprinted with black ink on one side and plain on other side, supplied as: NDC 85509-1203-3 Bottles of 30 tablets NDC 85509-1203-1 Bottles of 60 tablets Storage: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Store in the original container and keep the bottle tightly closed to protect from moisture. Dispense in a tight container if package is subdivided. Repackaged/Relabeled by: PHOENIX RX LLC Hatboro, PA 19040