Naproxen

1 INDICATIONS AND USAGE Naproxen tablets and naproxen sodium tablets are indicated for: the relief of the signs and symptoms of: • rheumatoid arthritis • osteoarthritis • ankylosing spondylitis • Polyarticular Juvenile Idiopathic Arthritis Naproxen tablets and naproxen sodium tablets are also indicated for: the relief of signs and symptoms of: • tendonitis • bursitis • acute gout the management of: • pain • primary dysmenorrhea Naproxen tablets and naproxen sodium tablets are non-steroidal anti-inflammatory drugs indicated for: the relief of the signs and symptoms of: • rheumatoid arthritis • osteoarthritis • ankylosing spondylitis • polyarticular juvenile idiopathic arthritis Naproxen tablets and naproxen sodium tablets are also indicated for: the relief of signs and symptoms of: • tendonitis • bursitis • acute gout the management of: • pain • primary dysmenorrhea

12.1 Mechanism of Action Naproxen has analgesic, anti-inflammatory, and antipyretic properties. Naproxen sodium has been developed as a more rapidly absorbed formulation of naproxen for use as an analgesic. The mechanism of action of naproxen, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). 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 a decrease of prostaglandins in peripheral tissues.

2 DOSAGE AND ADMINISTRATION Use the lowest effective dosage for shortest duration consistent with individual patient treatment goals. ( 2.1 ) Rheumatoid Arthritis, Osteoarthritis, and Ankylosing Spondylitis Naproxen tablets 250 mg (one-half tablet) 500 mg twice daily Naproxen sodium tablets 275 mg (one-half tablet) 550 mg twice daily The dose may be adjusted up or down depending on the clinical response of the patient. In patients who tolerate lower doses well, the dose may be increased to naproxen 1500 mg/ day for up to 6 months. Polyarticular Juvenile Idiopathic Arthritis Naproxen tablets may not allow for the flexible dose titration needed in pediatric patients with polyarticular juvenile idiopathic arthritis. A liquid formulation may be more appropriate. Recommended total daily dose of naproxen is approximately 10 mg/kg given in 2 divided doses. Dosing with naproxen tablets is not appropriate for children weighing less than 50 kilograms. Management of Pain, Primary Dysmenorrhea, and Acute Tendonitis and Bursitis Recommended starting dose 550 mg of naproxen sodium as naproxen sodium tablets followed by 550 mg every 12 hours or 275 mg every 6 to 8 hours as required. The initial total daily dose should not exceed 1375 mg of naproxen sodium. Thereafter, the total daily dose should not exceed 1100 mg of naproxen sodium. Naproxen sodium tablets are recommended for the management of acute painful conditions when prompt onset of pain relief is desired. Acute Gout Recommended starting dose 750 mg of naproxen tablets followed by 250 mg every 8 hours until the attack has subsided. Naproxen sodium tablets may also be used at a starting dose of 825 mg followed by 275 mg every 8 hours. 2.1 General Dosing Instructions Carefully consider the potential benefits and risks of naproxen tablets and naproxen sodium tablets and other treatment options before deciding to use naproxen tablets and naproxen sodium tablets. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals [ see Warnings and Precautions ( 5 ) ]. After observing the response to initial therapy with naproxen tablets or naproxen sodium tablets, the dose and frequency should be adjusted to suit an individual patient’s needs. Naproxen-containing products such as naproxen and naproxen sodium tablets, and other naproxen products should not be used concomitantly since they all circulate in the plasma as the naproxen anion. 2.2 Rheumatoid Arthritis, Osteoarthritis and Ankylosing Spondylitis The recommended dosages of naproxen tablets and naproxen sodium tablets are shown in Table 1. Table 1: Recommended dosages for naproxen tablets and naproxen sodium tablets Naproxen tablets 250 mg (one half tablet) 500 mg twice daily Naproxen sodium tablets 275 mg (one half tablet) 550 mg (naproxen 500 mg with 50 mg sodium) twice daily During long-term administration, the dose of naproxen may be adjusted up or down depending on the clinical response of the patient. A lower daily dose may suffice for long-term administration. The morning and evening doses do not have to be equal in size and administration of the drug more frequently than twice daily does not generally make a difference in response. In patients who tolerate lower doses well, the dose may be increased to naproxen 1500 mg/day for limited periods of up to 6 months when a higher level of anti-inflammatory/analgesic activity is required. When treating such patients with naproxen 1500 mg/day, the physician should observe sufficient increased clinical benefits to offset the potential increased risk. 2.3 Polyarticular Juvenile Idiopathic Arthritis Naproxen solid-oral dosage forms may not allow for the flexible dose titration needed in pediatric patients with polyarticular juvenile idiopathic arthritis. A liquid formulation may be more appropriate for weight-based dosing and due to the need for dose flexibility in children. In pediatric patients, doses of 5 mg/kg/day produced plasma levels of na

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Cardiovascular Thrombotic Events [ see Warnings and Precautions ( 5.1 ) ] • GI Bleeding, Ulceration, and Perforation [ see Warnings and Precautions ( 5.2 ) ] • Hepatotoxicity [ see Warnings and Precautions ( 5.3 ) ] • Hypertension [ see Warnings and Precautions ( 5.4 ) ] • Heart Failure and Edema [ see Warnings and Precautions ( 5.5 ) ] • Renal Toxicity and Hyperkalemia [ see Warnings and Precautions ( 5.6 ) ] • Anaphylactic Reactions [ see Warnings and Precautions ( 5.7 ) ] • Serious Skin Reactions [ see Warnings and Precautions ( 5.9 ) ] • Hematologic Toxicity [ see Warnings and Precautions ( 5.12 ) ] Most common adverse reactions to naproxen were dyspepsia, abdominal pain, nausea, headache, rash, ecchymosis, and edema. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Glenmark Pharmaceuticals Inc., USA at 1 (888) 721-7115 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse reactions reported in controlled clinical trials in 960 patients treated for rheumatoid arthritis or osteoarthritis are listed below. In general, reactions in patients treated chronically were reported 2 to 10 times more frequently than they were in short-term studies in the 962 patients treated for mild to moderate pain or for dysmenorrhea. The most frequent complaints reported related to the gastrointestinal tract. A clinical study found gastrointestinal reactions to be more frequent and more severe in rheumatoid arthritis patients taking daily doses of 1500 mg naproxen compared to those taking 750 mg naproxen. In controlled clinical trials with about 80 pediatric patients and in well-monitored, open-label studies with about 400 pediatric patients with polyarticular juvenile idiopathic arthritis treated with naproxen, the incidence of rash and prolonged bleeding times were greater, the incidence of gastrointestinal and central nervous system reactions were about the same, and the incidence of other reactions were lower in pediatric patients than in adults. In patients taking naproxen in clinical trials, the most frequently reported adverse experiences in approximately 1% to 10% of patients were: Gastrointestinal (GI) Experiences, including: heartburn*, abdominal pain*, nausea*, constipation*, diarrhea, dyspepsia, stomatitis Central Nervous System: headache*, dizziness*, drowsiness*, lightheadedness, vertigo Dermatologic: pruritus (itching)*, skin eruptions*, ecchymoses*, sweating, purpura Special Senses: tinnitus*, visual disturbances, hearing disturbances Cardiovascular: edema*, palpitations General: dyspnea*, thirst *Incidence of reported reaction between 3% and 9%. Those reactions occurring in less than 3% of the patients are unmarked. In patients taking NSAIDs, the following adverse experiences have also been reported in approximately 1% to 10% of patients. Gastrointestinal (GI) Experiences, including: flatulence, 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, vomiting Hepatobiliary: jaundice Hemic and Lymphatic: melena, thrombocytopenia, agranulocytosis Nervous System: inability to concentrate Dermatologic: skin rashes 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of naproxen. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate

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 tablets and naproxen sodium 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 tablets and naproxen sodium 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 tablets and naproxen sodium tablets are contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity). ( 5.8 ) Serious Skin Reactions : Discontinue naproxen tablets and naproxen sodium 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 tablets and naproxen sodium tablets, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal 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 or symptoms of anemia. ( 5.12 , 7 ) 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

4 CONTRAINDICATIONS Naproxen tablets and naproxen sodium tablets are contraindicated in the following patients: • Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to naproxen or any components of the drug product [ see Warnings and Precautions ( 5.7 , 5.9 ) ] • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [ see Warnings and Precautions ( 5.7 , 5.8 ) ] • In the setting of coronary artery bypass graft (CABG) surgery [ see Warnings and Precautions ( 5.1 ) ] • Known hypersensitivity to naproxen or any components of the drug product ( 4 ) • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs ( 4 ) • In the setting of CABG surgery ( 4 )

10 OVERDOSAGE Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [ see Warnings and Precautions ( 5.1 , 5.2 ) ].Because naproxen sodium may be rapidly absorbed, high and early blood levels should be anticipated. A few patients have experienced convulsions, 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 [ see Warnings and Precautions ( 5.1 , 5.2 , 5.4 , 5.6 ) ]. Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. For additional information about overdosage treatment contact a poison control center (1-800-222-1222).