Naproxen

1 INDICATIONS AND USAGE Naproxen Tablets are indicated for: the relief of the signs and symptoms of: rheumatoid arthritis osteoarthritis ankylosing spondylitis polyarticular juvenile idiopathic arthritis tendonitis bursitis acute gout the management of: pain primary dysmenorrhea Naproxen 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 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 375 mg 500 mg twice daily twice daily 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 1,500 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. Acute Gout Recommended starting dose 750 mg of naproxen Tablets followed by 250 mg every 8 hours until the attack has subsided. 2.1 General Dosing Instructions Carefully consider the potential benefits and risks of naproxen Tablets and other treatment options before deciding to use naproxen 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, the dose and frequency should be adjusted to suit an individual patient’s needs. Naproxen-containing products such as naproxen 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 are shown in Table 1. Table 1: Recommended dosages for Naproxen Tablets Naproxen Tablets 250 mg 375 mg 500 mg twice daily twice daily 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 1,500 mg per 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 1,500 mg per 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 naproxen similar to those seen in adults taking 500 mg of naproxen [see Clinical Pharmacology (12) ]. The 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. 2.4 Management of Pain, Primary Dysmenorrhea, and Acute Tendonitis and Bursitis The recommended starting dose of naproxen tablets is 500 mg followed by 250 mg (one half of a 500 mg naproxen tablet) every 6-8 hours as required. The total daily dose should not exceed 1,250 mg of naproxen. 2.5 Acute Gout The recommended starting dose is 750 mg of naproxen tablets followed by 250 mg every 8 hours until the attack has subsided. 2.6 Non-Interchangeability with Other Formulations of Naproxen Different dose strengths and formulations (e.g., tablets, suspension) of naproxen are not interchangeable. This difference should be taken in…

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 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 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 are contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity). (5.8) Serious Skin Reactions: Discontinue naproxen 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, 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 contraindicated in the setting of CABG [ see Contraindications (4) ]. Post-MI Patients Observational studies conducted in the Danish National Registry have demo…

4 CONTRAINDICATIONS Naproxen 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)

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 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 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 tablets and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions (5.12) ]. Naproxen tablets are not substitutes for low dose aspirin for cardiovascular protection. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact: NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol). In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention: During concomitant use of naproxen tablets and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of naproxen tablets and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ see Warnings and Precautions (5.6) ]. When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriureti…

8.1 Pregnancy Risk Summary Use of NSAIDs, including naproxen tablets can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of naproxen tablets use between about 20 and 30 weeks of gestation, and avoid naproxen tablets use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations , Data ). Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including naproxen 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. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies in rats, rabbits, and mice no evidence of teratogenicity or fetal harm when naproxen was administered during the period of organogenesis at doses 0.13, 0.26, and 0.6 times the maximum recommended human daily dose of 1,500 mg/day, respectively [ 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. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is 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 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 tablets treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue naproxen tablets, and follow up according to clinical practice (see Data ). Labor or Delivery There are no studies on the effects of naproxen tablets during labor or delivery. In animal studies, NSAIDS, including naproxen, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data Human Data There is some evidence to suggest that when inhibitors of prostaglandin synthesis are used to delay preterm labor, there is an increased risk of neonatal complications such as necrotizing enterocolitis, patent ductus arteriosus, and intracranial hemorrhage. Naproxen treatment given in late pregnancy to delay parturition has been associated with persistent pulmonary hypertension, renal dysfunction, and abnormal prostaglandin E levels in preterm infants. Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly starting at 30-weeks of gestation, or third trimester) should be avoided. Premature Cl…

8.3 Females and Males of Reproductive Potential Infertility Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including naproxen tablets, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including naproxen 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 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 ScieGen Pharmaceuticals, Inc. at 1-855-724-3436 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 1,500 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 C entral Nervous System: headache * , dizziness * , drowsiness * , lightheadedness, vertigo Dermatologic: pruritus (itching) * , skin eruptions * , ecchymoses * , sweating, purpura Special Senses: tinnitus * , visual disturbances, hearing disturbances C ardiovascular: 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 their frequency…