Hiposul

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

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…

12.2 Pharmacodynamics In a healthy volunteer study, 10 days of concomitant administration of naproxen 220 mg once-daily with low-dose immediate-release aspirin (81 mg) showed an interaction with the antiplatelet activity of aspirin as measured by % serum thromboxane B 2 inhibition at 24 hours following the day 10 dose [98.7% (aspirin alone) vs 93.1% (naproxen and aspirin)]. The interaction was observed even following discontinuation of naproxen on day 11 (while aspirin dose was continued) but normalized by day 13. In the same study, the interaction was greater when naproxen was administered 30 minutes prior to aspirin [98.7% vs 87.7%] and minimal when aspirin was administered 30 minutes prior to naproxen [98.7% vs 95.4%]. Following administration of naproxen 220 mg twice-daily with low-dose immediate- release aspirin (first naproxen dose given 30 minutes prior to aspirin), the interaction was minimal at 24 h following day 10 dose [98.7% vs 95.7%]. However, the interaction was more prominent after discontinuation of naproxen (washout) on day 11 [98.7% vs 84.3%] and did not normalize completely by day 13 [98.5% vs 90.7%] [ see Drug Interactions ( 7 ) ].

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…

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 )

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…

7 DRUG INTERACTIONS See Table 1 for clinically significant drug interactions with naproxen. Table 1: Clinically Significant Drug Interactions with naproxen Drugs That Interfere with Hemostasis Clinical Impact: • Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants have an increased 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. Intervention: Monitor patients with concomitant use of naproxen tablets or naproxen sodium 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 ( 5.12 ) ]. Aspirin Clinical Impact: A pharmacodynamic (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 12.2 Pharmacodynamics) . 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…