NAPROSYN- naproxen_suspension

Naproxen has analgesic, anti-inflammatory, and antipyretic properties. 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. 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 B2 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%] and minimal when aspirin was administered 30 minutes prior to naproxen [98. 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. However, the interaction was more prominent after discontinuation of naproxen (washout) on day 11 [98. 3%] and did not normalize completely by day 13 [98. [ see Drug Interactions ( 7 Naproxen is rapidly and completely absorbed from the gastrointestinal tract with an in vivo bioavailability of 95%. The elimination half-life of naproxen ranges from 12 to 17 hours. Steady-state levels of naproxen are reached in 4 to 5 days, and the degree of naproxen accumulation is consistent with this half-life. Absorption Peak plasma levels of naproxen given as NAPROSYN Suspension are attained in 1 to 4 hours. NAPROSYN Suspension Naproxen Tablets 500 mg C max 64. 3 AUC 0en dasht 1249 1218 Distribution Naproxen has a volume of distribution of 0. At therapeutic levels naproxen is greater than 99% albumin-bound. At doses of naproxen greater than 500 mg/day there is less than proportional increase in plasma levels due to an increase in clearance caused by saturation of plasma protein binding at higher doses (average trough Css 36. 4 mg/L with 500, 1000 and 1500 mg daily doses of naproxen, respectively). The naproxen anion has been found in the milk of lactating women at a concentration equivalent to approximately 1% of maximum naproxen concentration in plasma [ see Use in Specific Populations ( 8. 2 Elimination Metabolism Naproxen is extensively metabolized in the liver to 6-0-desmethyl naproxen, and both parent and metabolites do not induce metabolizing enzymes. Both naproxen and 6-0-desmethyl naproxen are further metabolized to their respective acylglucuronide conjugated metabolites. Excretion The clearance of naproxen is 0. 13 mL/min/kg. Approximately 95% of the naproxen from any dose is excreted in the urine, primarily as naproxen (<1%), 6-0-desmethyl naproxen (<1%) or their conjugates (66% to 92%). The plasma half-life of the naproxen anion in humans ranges from 12 to 17 hours. The corresponding half-lives of both naproxen's metabolites and conjugates are shorter than 12 hours, and their rates of excretion have been found to coincide closely with the rate of naproxen clearance from the plasma. Small amounts, 3% or less of the administered dose, are excreted in the feces. In patients with renal failure metabolites may accumulate [ see Warnings and Precautions ( 5. 6 Specific Populations Pediatric In pediatric patients aged 5 to 16 years with arthritis, plasma naproxen levels following a 5 mg/kg single dose of naproxen suspension [ see Dosage and Administration ( 2 Geriatric Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly, although the unbound fraction is <1% of the total naproxen concentration. Unbound trough naproxen concentrations in elderly subjects have been reported to range from 0. 19% of total naproxen concentration, compared with 0. 075% in younger subjects. Hepatic Impairment Naproxen pharmacokinetics has not been determined in subjects with hepatic insufficiency. Chronic alcoholic liver disease and probably other diseases with decreased or abnormal plasma proteins (albumin) reduce the total plasma concentration of naproxen, but the plasma concentration of unbound naproxen is increased. Renal Impairment Naproxen pharmacokinetics has not been determined in subjects with renal insufficiency. Given that naproxen, its metabolites and conjugates are primarily excreted by the kidney, the potential exists for naproxen metabolites to accumulate in the presence of renal insufficiency. Elimination of naproxen is decreased in patients with severe renal impairment. Drug Interaction Studies Aspirin see Drug Interactions ( 7.

NAPROSYN (naproxen) Suspension is 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 NAPROSYN Suspension is a non-steroidal anti-inflammatory drug 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.

Use the lowest effective dose for shortest duration consistent with individual patient treatment goals. ( 2 Rheumatoid Arthritis, Osteoarthritis, and Ankylosing Spondylitis NAPROSYN Suspension 250 mg (10 mL) 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 Recommended total daily dose of naproxen is approximately 10 mg/kg given in 2 divided doses. The following table may be used as a guide for dosing of naproxen suspension: Patient's Weight Dose Administered as 13 kg (29 lb) 62. 5 mg twice daily 2. 5 mL (1/2 tsp) twice daily 25 kg (55 lb) 125 mg twice daily 5. 0 mL (1 tsp) twice daily 38 kg (84 lb) 187. 5 mg twice daily 7. 5 mL (1 1/2 tsp) twice daily Management of Pain, Primary Dysmenorrhea, and Acute Tendonitis and Bursitis The recommended starting dose of NAPROSYN Suspension is 500 mg (20 mL), followed by 250 mg (10 mL) every 6 to 8 hours as required. Acute Gout The recommended starting dose is 750 mg (30 mL) of NAPROSYN Suspension followed by 250 mg (10 mL) every 8 hours until the attack has subsided. Carefully consider the potential benefits and risks of NAPROSYN Suspension and other treatment options before deciding to use NAPROSYN Suspension. 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 NAPROSYN Suspension, the dose and frequency should be adjusted to suit an individual patient's needs. Always use a calibrated measuring device when administering NAPROSYN suspension to ensure the dose is measured and administered accurately. A household teaspoon or tablespoon is not an adequate measuring device, especially when one-half of a teaspoonful is to be measured. Given the variability of the household spoon measure, it is strongly recommended that caregivers obtain and use a calibrated measuring device. Health care providers should recommend an appropriate measuring device that can measure and deliver the prescribed dose accurately, and instruct caregivers to use extreme caution in measuring the dosage. Naproxen-containing products such as NAPROSYN suspension, and other naproxen products should not be used concomitantly since they all circulate in the plasma as the naproxen anion. The recommended dosage of NAPROSYN suspension is shown in Table 1. Table 1: Recommended dosages of NAPROSYN Suspension NAPROSYN Suspension 250 mg (10 mL) twice daily NAPROSYN Suspension should be shaken gently before use. 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. The use of NAPROSYN Suspension is recommended for juvenile arthritis in children 2 years or older because it allows for more flexible dose titration based on the child's weight. 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. 3 The recommended total daily dose of naproxen is approximately 10 mg/kg given in 2 divided doses (i. , 5 mg/kg given twice a day). A measuring cup marked in 1/2 teaspoon and 2. 5 milliliter increments is provided with the NAPROSYN Suspension. The following table may be used as a guide for dosing of NAPROSYN Suspension: Patient's Weight Dose Administered as 13 kg (29 lb) 62. 5 mL (1 1/2 tsp) twice daily The recommended starting dose of NAPROSYN Suspension is 500 mg (20 mL), followed by 250 mg (10 mL) every 6 to 8 hours as required. The total daily dose should not exceed 1250 mg (50 mL). The recommended starting dose is 750 mg (30 mL) of NAPROSYN Suspension followed by 250 mg (10 mL) every 8 hours until the attack has subsided. Different dose strengths and formulations (e. , tablets, suspension) of naproxen are not interchangeable. This difference should be taken into consideration when changing strengths or formulations.

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. 1 To report SUSPECTED ADVERSE REACTIONS, contact Athena Bioscience LLC at 1-833-284-3622or FDA at 1-800-FDA-1088 or 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 are: Gastrointestinal (GI) Experiences, including: Central Nervous System: Dermatologic: Special Senses: Cardiovascular: General: *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: General: 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 or establish a causal relationship to drug exposure. The following are additional adverse experiences reported in <1% of patients taking naproxen during clinical trials and through postmarketing reports. Those adverse reactions observed through postmarketing reports are italicized. Body as a Whole Cardiovascular Gastrointestinal Hepatobiliary Hemic and Lymphatic Metabolic and Nutritional Nervous System Respiratory Dermatologic Special Senses Urogenital Reproduction (female) In patients taking NSAIDs, the following adverse experiences have also been reported in <1% of patients. Body as a Whole Cardiovascular Gastrointestinal Hepatobiliary Hemic and Lymphatic Metabolic and Nutritional Nervous System Respiratory Dermatologic Special Senses Urogenital.

NAPROSYN Suspension is contraindicated in the following patients: Known hypersensitivity (e. , anaphylactic reactions and serious skin reactions) to naproxen or any components of the drug product [ see Warnings and Precautions ( 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. 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.

Infertility: 8. 3 Renal Impairment: 8. 7 Risk Summary Use of NSAIDs, including NAPROSYN Suspension, 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 NAPROSYN Suspension use between about 20 and 30 weeks of gestation, and avoid NAPROSYN Suspension 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 NAPROSYN Suspension, 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. 6 times the maximum recommended human daily dose of 1500 mg/day, respectively. 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. 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 NAPROSYN Suspension, 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 NAPROSYN Suspension treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue NAPROSYN Suspension, and follow up according to clinical practice (see Data Labor or Delivery There are no studies on the effects of NAPROSYN Suspension 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 Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain. Animal data Reproduction studies have been performed in rats at 20 mg/kg/day (0. 13 times the maximum recommended human daily dose of 1500 mg/day based on body surface area comparison), rabbits at 20 mg/kg/day (0. 26 times the maximum recommended human daily dose, based on body surface area comparison), and mice at 170 mg/kg/day (0. 6 times the maximum recommended human daily dose based on body surface area comparison) with no evidence of impaired fertility or harm to the fetus due to the drug. Risk Summary The naproxen anion has been found in the milk of lactating women at a concentration equivalent to approximately 1% of maximum naproxen concentration in plasma. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for NAPROSYN Suspension and any potential adverse effects on the breastfed infant from the NAPROSYN Suspension or from the underlying maternal condition. Infertility Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including NAPROSYN Suspension, 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 NAPROSYN Suspension, in women who have difficulties conceiving or who are undergoing investigation of infertility. Safety and effectiveness in pediatric patients below the age of 2 years have not been established. Pediatric dosing recommendations for polyarticular juvenile idiopathic arthritis are based on well-controlled studies. There are no adequate effectiveness or dose-response data for other pediatric conditions, but the experience in polyarticular juvenile idiopathic arthritis and other use experience have established that single doses of 2. 5 to 5 mg/kg (as naproxen suspension), with total daily dose not exceeding 15 mg/kg/day, are well tolerated in pediatric patients over 2 years of age. The hepatic and renal tolerability of long-term naproxen administration was studied in two double-blind clinical trials involving 586 patients. Of the patients studied, 98 patients were age 65 and older and 10 of the 98 patients were age 75 and older. Naproxen was administered at doses of 375 mg twice daily or 750 mg twice daily for up to 6 months. Transient abnormalities of laboratory tests assessing hepatic and renal function were noted in some patients, although there were no differences noted in the occurrence of abnormal values among different age groups. Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [ see Warnings and Precautions ( 5. 14 Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly. The clinical significance of this finding is unclear, although it is possible that the increase in free naproxen concentration could be associated with an increase in the rate of adverse events per a given dosage in some elderly patients. Caution is advised when high doses are required and some adjustment of dosage may be required in elderly patients. As with other drugs used in the elderly, it is prudent to use the lowest effective dose. Experience indicates that geriatric patients may be particularly sensitive to certain adverse effects of nonsteroidal anti-inflammatory drugs. Elderly or debilitated patients seem to tolerate peptic ulceration or bleeding less well when these events do occur. Most spontaneous reports of fatal GI events are in the geriatric population [ see Warnings and Precautions ( 5. 6 Naproxen is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Geriatric patients may be at a greater risk for the development of a form of renal toxicity precipitated by reduced prostaglandin formation during administration of nonsteroidal anti-inflammatory drugs [ see Warnings and Precautions ( 5. 6 Caution is advised when high doses are required and some adjustment of dosage may be required in these patients. It is prudent to use the lowest effective dose [ see Clinical Pharmacology ( 12. 3 Naproxen-containing products are not recommended for use in patients with moderate to severe and severe renal impairment (creatinine clearance <30 mL/min) [ see Warnings and Precautions ( 5.

See Table 2 for clinically significant drug interactions with naproxen. Table 2: 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 NAPROSYN Suspension with anticoagulants (e. , warfarin), antiplatelet agents (e. , 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 see Clinical Pharmacology ( 12. 2 enteric-coated 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. see Warnings and Precautions ( 5. 12 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). Intervention: During concomitant use of NAPROSYN Suspension and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of NAPROSYN Suspension 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 natriuretic effect of loop diuretics (e. , furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of NAPROSYN Suspension with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ see Warnings and Precautions ( 5. 6 Digoxin Clinical Impact: The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin Intervention: During concomitant use of NAPROSYN Suspension and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of NAPROSYN Suspension and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e. , neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of NAPROSYN Suspension and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of NAPROSYN Suspension and cyclosporine may increase cyclosporine's nephrotoxicity. Intervention: During concomitant use of NAPROSYN Suspension and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of naproxen with other NSAIDs or salicylates (e. , diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [ see Warnings and Precautions ( 5. 2 Intervention: The concomitant use of naproxen with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Impact: Concomitant use of NAPROSYN Suspension and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of NAPROSYN Suspension and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Antacids and Sucralfate Clinical Impact: Concomitant administration of some antacids (magnesium oxide or aluminum hydroxide) and sucralfate can delay the absorption of naproxen. Intervention: Concomitant administration of antacids such as magnesium oxide or aluminum hydroxide, and sucralfate with NAPROSYN Suspension is not recommended. Cholestyramine Clinical Impact: Concomitant administration of cholestyramine can delay the absorption of naproxen. Intervention: Concomitant administration of cholestyramine with NAPROSYN Suspension is not recommended. Probenecid Clinical Impact: Probenecid given concurrently increases naproxen anion plasma levels and extends its plasma half-life significantly. Intervention: Patients simultaneously receiving NAPROSYN Suspension and probenecid should be observed for adjustment of dose if required. Other albumin-bound drugs Clinical Impact: Naproxen is highly bound to plasma albumin; it thus has a theoretical potential for interaction with other albumin-bound drugs such as coumarin-type anticoagulants, sulphonylureas, hydantoins, other NSAIDs, and aspirin [ see Warnings and Precautions ( 5. 2 Intervention: Patients simultaneously receiving NAPROSYN Suspension and a hydantoin, sulphonamide or sulphonylurea should be observed for adjustment of dose if required. Drug/Laboratory Test Interactions Bleeding times Clinical Impact: Naproxen may decrease platelet aggregation and prolong bleeding time. Intervention: This effect should be kept in mind when bleeding times are determined. Porter-Silber test Clinical Impact: The administration of naproxen may result in increased urinary values for 17-ketogenic steroids because of an interaction between the drug and/or its metabolites with m-di-nitrobenzene used in this assay. Intervention: Although 17-hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be artifactually altered, it is suggested that therapy with naproxen be temporarily discontinued 72 hours before adrenal function tests are performed if the Porter-Silber test is to be used. Urinary assays of 5-hydroxy indoleacetic acid (5HIAA) Clinical Impact: Naproxen may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA). Intervention: This effect should be kept in mind when urinary 5-hydroxy indoleacetic acid is determined. Drugs that Interfere with Hemostasis (e. warfarin, aspirin, SSRIs/SNRIs): 7 ACE inhibitors, Angiotensin Receptor Blockers (ARB), or Beta-Blockers: 7 ACE Inhibitors and ARBs: 7 Diuretics: 7 Digoxin: 7.

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. 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) Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. 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. For additional information about overdosage treatment contact a poison control center (1-800-222-1222).
NONCLINICAL TOXICOLOGY
Carcinogenesis A 2-year study was performed in rats to evaluate the carcinogenic potential of naproxen at rat doses of 8, 16, and 24 mg/kg/day (0.05, 0.1, and 0.16 times the maximum recommended human daily dose of 1500 mg/day based on a body surface area comparison). No evidence of tumorigenicity was found. Mutagenesis Naproxen tested positive in the in vivo sister chromatid exchange assay for but was not mutagenic in the in vitro bacterial reverse mutation assay (Ames test). Impairment of Fertility Male rats were treated with 2, 5, 10, and 20 mg/kg naproxen by oral gavage for 60 days prior to mating and female rats were treated with the same doses for 14 days prior to mating and for the first 7 days of pregnancy. There were no adverse effects on fertility noted (up to 0.13 times the MRDH based on body surface area).
CLINICAL STUDIES
Naproxen has been studied in patients with rheumatoid arthritis, osteoarthritis, polyarticular juvenile idiopathic arthritis, ankylosing spondylitis, tendonitis and bursitis, and acute gout. Improvement in patients treated for rheumatoid arthritis was demonstrated by a reduction in joint swelling, a reduction in duration of morning stiffness, a reduction in disease activity as assessed by both the investigator and patient, and by increased mobility as demonstrated by a reduction in walking time. Generally, response to naproxen has not been found to be dependent on age, sex, severity or duration of rheumatoid arthritis. In patients with osteoarthritis, the therapeutic action of naproxen has been shown by a reduction in joint pain or tenderness, an increase in range of motion in knee joints, increased mobility as demonstrated by a reduction in walking time, and improvement in capacity to perform activities of daily living impaired by the disease. In a clinical trial comparing standard formulations of naproxen 375 mg twice a day (750 mg a day) vs 750 mg twice a day (1500 mg/day), 9 patients in the 750 mg group terminated prematurely because of adverse events. Nineteen patients in the 1500 mg group terminated prematurely because of adverse events. Most of these adverse events were gastrointestinal events. In clinical studies in patients with rheumatoid arthritis, osteoarthritis, and polyarticular juvenile idiopathic arthritis, naproxen has been shown to be comparable to aspirin and indomethacin in controlling the aforementioned measures of disease activity, but the frequency and severity of the milder gastrointestinal adverse effects (nausea, dyspepsia, heartburn) and nervous system adverse effects (tinnitus, dizziness, lightheadedness) were less in naproxen-treated patients than in those treated with aspirin or indomethacin. In patients with ankylosing spondylitis, naproxen has been shown to decrease night pain, morning stiffness and pain at rest. In double-blind studies the drug was shown to be as effective as aspirin, but with fewer side effects. In patients with acute gout, a favorable response to naproxen was shown by significant clearing of inflammatory changes (e.g., decrease in swelling, heat) within 24 to 48 hours, as well as by relief of pain and tenderness. Naproxen has been studied in patients with mild to moderate pain secondary to postoperative, orthopedic, postpartum episiotomy and uterine contraction pain and dysmenorrhea. Onset of pain relief can begin within 1 hour in patients taking naproxen. Analgesic effect was shown by such measures as reduction of pain intensity scores, increase in pain relief scores, decrease in numbers of patients requiring additional analgesic medication, and delay in time to remedication. The analgesic effect has been found to last for up to 12 hours. Naproxen may be used safely in combination with gold salts and/or corticosteroids; however, in controlled clinical trials, when added to the regimen of patients receiving corticosteroids, it did not appear to cause greater improvement over that seen with corticosteroids alone. Whether naproxen has a "steroid-sparing" effect has not been adequately studied. When added to the regimen of patients receiving gold salts, naproxen did result in greater improvement. Its use in combination with salicylates is not recommended because there is evidence that aspirin increases the rate of excretion of naproxen and data are inadequate to demonstrate that naproxen and aspirin produce greater improvement over that achieved with aspirin alone. In addition, as with other NSAIDs, the combination may result in higher frequency of adverse events than demonstrated for either product alone. In 51

Athena Bioscience, LLC

NAPROSYN- naproxen_suspension Product manual source documgent