Naproxen

RECENT MAJOR CHANGES Warnings and Precautions (5.9) 11/2024

1 INDICATIONS AND USAGE Naproxen oral 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 Naproxen oral 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

2 DOSAGE AND ADMINISTRATION Use the lowest effective dose for shortest duration consistent with individual patient treatment goals. ( 2 ) Rheumatoid Arthritis, Osteoarthritis, and Ankylosing Spondylitis Naproxen Suspension 250 mg (10 mL) or 375 mg (15 mL) or 500 mg (20 mL) 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 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 Naproxen 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 Naproxen Suspension followed by 250 mg (10 mL) every 8 hours until the attack has subsided. 2.1 General Dosing Instructions Carefully consider the potential benefits and risks of Naproxen Suspension and other treatment options before deciding to use Naproxen 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 Naproxen Suspension, the dose and frequency should be adjusted to suit an individual patient’s needs. Always use a calibrated measuring device when administering Naproxen 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 Naproxen Suspension, 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 dosage of Naproxen Suspension is shown in Table 1. Table 1: Recommended dosages of Naproxen Suspension Naproxen Suspension 250 mg (10 mL) or 375 mg (15 mL) or 500 mg (20 mL) twice daily twice daily twice daily Naproxen 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 the administration of the drug more frequently than twice daily is not necessary. 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 The use of Naproxen Suspension is recommended for juvenile arthritis in children 2 years or older because it allows for mor …

3 DOSAGE FORMS AND STRENGTHS Naproxen oral suspension, USP: 125 mg/5 mL (contains 38.95 mg sodium): Available in 1 pint (473 mL) light-resistant bottles. Naproxen oral suspension, USP: 125 mg/5 mL (contains 38.95 mg sodium)

4 CONTRAINDICATIONS Naproxen oral suspension is 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 )

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 Cardiovascular Thrombotic Events ) ] GI Bleeding, Ulceration, and Perforation [ see Warnings and Precautions ( 5.2 ) ] Hepatotoxicity [ see Warnings and Precautions ( 5.3 Hepatotoxicity ) ] Hypertension [ see Warnings and Precautions ( 5.4 Hypertension ) ] Heart Failure and Edema [ see Warnings and Precautions ( 5.5 Heart Failure and Edema ) ] Renal Toxicity and Hyperkalemia [ see Warnings and Precautions ( 5.6 Renal Toxicity and Hyperkalemia ) ] Anaphylactic Reactions [ see Warnings and Precautions ( 5.7 ) ] Serious Skin Reactions [ see Warnings and Precautions ( 5.9 ) ] Hematologic Toxicity [ see Warnings and Precautions ( 5.11 ) ] Most common adverse reactions to naproxen were dyspepsia, abdominal pain, nausea, headache, rash, ecchymosis, and edema. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Pharmaceutical Associates, Inc. at 1-800-845-8210 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 are: 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 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 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. …

7 DRUG INTERACTIONS 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 Naproxen Suspension 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 ( 5.11 ) ]. 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 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 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 Suspension and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions ( 5.11 ) ]. Naproxen suspension is not a substitute 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 Suspension and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of Naproxen 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 Renal Toxicity and Hyperkalemia ) ]. 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- …

8 USE IN SPECIFIC POPULATIONS Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal of naproxen oral suspension in women who have difficulties conceiving. ( 8.3 ) Renal Impairment: Naproxen-containing products are not recommended for use in patients with moderate to severe and severe renal impairment (creatinine clearance <30 mL/min). ( 8.7 ) 8.1 Pregnancy Risk Summary Use of NSAIDs, including naproxen oral 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 naproxen oral suspension use between about 20 and 30 weeks of gestation, and avoid naproxen oral 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 naproxen oral 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 0.13, 0.26, and 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. 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 oral 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 naproxen oral suspension treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue naproxen oral suspension, and follow up according to clinical practice (see Data). Labor or Delivery There are no studies on the effects of naproxen oral 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 …

12.1 Mechanism of Action 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.

11 DESCRIPTION Naproxen oral suspension, USP is available as a light orange-colored, pineapple-orange flavored homogenous suspension containing 125 mg/5 mL of naproxen USP for oral administration. Naproxen is a propionic acid derivative related to the arylacetic acid group of nonsteroidal anti-inflammatory drugs. The chemical name is (S)-6-methoxy-α-methyl-2-naphthaleneacetic acid. The molecular weight is 230.26. Its molecular formula is C 14 H 14 O 3 , and it has the following chemical structure. Naproxen USP is a white to off-white crystalline powder. It is soluble in chloroform, in dehydrated alcohol, and in alcohol, sparingly soluble in ether, practically insoluble in water. The octanol/water partition coefficient of naproxen at pH 7.4 is 1.6 to 1.8. The inactive ingredients in naproxen oral suspension USP include art pineapple flavor, benzyl alcohol, FD&C yellow No. 6, fumaric acid, magnesium aluminum silicate, methylparaben, modified food starch (corn), nat orange flavor, noncrystallizing sorbitol solution, propylene glycol, purified water, sodium chloride (39 mg/5 mL, 0.667 mEq), sucrose, and xanthan gum. The pH of the suspension ranges from 2.2 to 3.7. str

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. 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 Cardiovascular Thrombotic Events, 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).

16 HOW SUPPLIED/STORAGE AND HANDLING Naproxen oral suspension, USP: 125 mg/5 mL (contains 38.95 mg sodium) is available as a light orange-colored opaque orange-pineapple flavored oral suspension in 1 pint (473 mL) light-resistant bottles. It is supplied as follows: One 473 mL bottle with child-resistant closure: NDC 69238-1730-2 Storage Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Avoid excessive heat above 40°C (104°F). Dispense in light-resistant containers. Shake gently before use.