NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS (naproxen)

NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS (naproxen)

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NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS (naproxen)

NAPROSYN (naproxen) tablets, EC-NAPROSYN (naproxen) delayed-release tablets and ANAPROX DS (naproxen sodium) tablets are nonsteroidal anti-inflammatory drugs available as follows:

NAPROSYN tablets are available as yellow tablets containing 500 mg of naproxen for oral administration.

EC-NAPROSYN delayed-release tablets are available as enteric-coated white tablets containing 375 mg of naproxen or 500 mg of naproxen for oral administration.

ANAPROX DS tablets are available as dark blue tablets containing 550 mg of naproxen sodium for oral administration.

Naproxen is a propionic acid derivative related to the arylacetic acid group of nonsteroidal anti-inflammatory drugs. The chemical names for naproxen and naproxen sodium are (S)-6-methoxy-α-methyl-2-naphthaleneacetic acid and (S)-6- methoxyα-methyl-2-naphthaleneacetic acid, sodium salt, respectively. Naproxen has a molecular weight of 230.26 and a molecular formula of C14H14O3. Naproxen sodium has a molecular weight of 252.23 and a molecular formula of C14H13NaO3.

Naproxen is an odorless, white to off-white crystalline substance. It is lipid-soluble, practically insoluble in water at low pH and freely soluble in water at high pH. The octanol/water partition coefficient of naproxen at pH 7.4 is 1.6 to 1.8. Naproxen sodium is a white to creamy white, crystalline solid, freely soluble in water at neutral pH.

Indications and usage

NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS 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

NAPROSYN Tablets and ANAPROX DS are also indicated for the relief of signs and symptoms of:

  • tendonitis
  • bursitis
  • acute gout
  • the management of pain
  • primary dysmenorrhea

Mechanism of Action

Naproxen has analgesic, anti-inflammatory, and antipyretic properties. ANAPROX DS (naproxen sodium) has been developed as a more rapidly absorbed formulation of naproxen for use as an analgesic.

The mechanism of action of naproxen, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2).

Naproxen is a potent inhibitor of prostaglandin synthesis in vitro. Naproxen concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because naproxen is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues.

Dosage and administration

Use the lowest effective dosage for shortest duration consistent with individual patient treatment goals

Rheumatoid Arthritis, Osteoarthritis, and Ankylosing Spondylitis

NAPROSYN Tablets250 mg (one-half tablet) 500 mgtwice daily
EC-NAPROSYN275 mg (one-half tablet) 550 mgtwice daily
ANAPROX DS375 mg or 500 mgtwice daily

To maintain the integrity of the enteric coating, the EC-NAPROSYN tablet should not be broken, crushed or chewed during ingestion.

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: NAPROSYN 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 NAPROSYN 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 ANAPROX DS 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. ANAPROX DS is recommended for the management of acute painful conditions when prompt onset of pain relief is desired.

Acute Gout: Recommended starting dose 750 mg of NAPROSYN Tablets followed by 250 mg every 8 hours until the attack has subsided. ANAPROX DS may also be used at a starting dose of 825 mg followed by 275 mg every 8 hours. EC-NAPROSYN is not recommended because of the delay in absorption.

Contraindications

  • Known hypersensitivity to naproxen or any components of the drug product
  • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs
  • In the setting of coronary artery bypass graft (CABG) surgery

Warnings and precautions

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. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible.

Gastrointestinal Bleeding, Ulceration, and Perforation: NSAIDs, including naproxen, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs

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.

Hypertension: Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure.

Heart Failure and Edema: Avoid use of NAPROSYN Tablets, EC-NAPROSYN and ANAPROX DS in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure.

Renal Toxicity: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of NAPROSYN Tablets, EC-NAPROSYN and ANAPROX DS in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function.

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Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs.

Exacerbation of Asthma Related to Aspirin Sensitivity: NAPROSYN Tablets, ECNAPROSYN and ANAPROX DS are contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity).

Serious Skin Reactions: Discontinue NAPROSYN Tablets, EC-NAPROSYN and ANAPROX DS at first appearance of skin rash or other signs of hypersensitivity.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue and evaluate clinically.

Fetal Toxicity: Limit use of NSAIDs, including NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS, 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.

Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia

Adverse reactions

Most common adverse reactions to naproxen were dyspepsia, abdominal pain, nausea, headache, rash, ecchymosis, and edema.

Drug interactions

Drugs that Interfere with Hemostasis (e.g. warfarin, aspirin, SSRIs/SNRIs): Monitor patients for bleeding who are concomitantly taking NAPROSYN Tablets, ECNAPROSYN or ANAPROX DS with drugs that interfere with hemostasis. Concomitant use of NAPROSYN Tablets, EC-NAPROSYN or ANAPROX DS and analgesic doses of aspirin is not generally recommended.

ACE inhibitors, Angiotensin Receptor Blockers (ARB), or Beta-Blockers: Concomitant use with NAPROSYN Tablets, EC-NAPROSYN or ANAPROX DS may diminish the antihypertensive effect of these drugs. Monitor blood pressure.

ACE Inhibitors and ARBs: Concomitant use with NAPROSYN Tablets, EC-NAPROSYN or ANAPROX DS in elderly, volume depleted, or those with renal impairment may result in deterioration of renal function. In such high risk patients, monitor for signs of worsening renal function.

Diuretics: NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects.

Digoxin: Concomitant use with NAPROSYN Tablets, EC-NAPROSYN or ANAPROX DS can increase serum concentration and prolong half-life of digoxin. Monitor serum digoxin levels.

Use in specific populations

Pregnancy: Use of NSAIDs, including NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS, 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 Tablets, EC-NAPROSYN, or ANAPROX DS use between about 20 and 30 weeks of gestation, and avoid NAPROSYN Tablets, EC-NAPROSYN, and ANAPROX DS use at about 30 weeks of gestation and later in pregnancy

Lactation: 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 Tablets, EC-NAPROSYN, or ANAPROX DS and any potential adverse effects on the breastfed infant from the NAPROSYN Tablets, EC-NAPROSYN, or ANAPROX DS or from the underlying maternal condition.

Pediatric Use: 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.

Geriatric use: 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.

Hepatic Impairment: 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.

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).

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.Because naproxen sodium may be rapidly absorbed, high and early blood levels should be anticipated.

A few patients have experienced convulsions, but it is not clear whether or not these were drug-related. It is not known what dose of the drug would be life threatening.

Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes.

Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.

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