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Category :

Antirheumatic, Anti – inflammatory ( nonsteroidal) Analgesic, Anti- gout agent ,Antipyretic, Antidysmenorrheal, Vascular headache prophylactic, vascular headache suppressant. ( USPDI 2005)

Composition :

Each tablet contains 250 mg of naproxen.

Chemistry :

The chemical name of naproxen is (S)- 6– methoxy- α methyl-2 – naphthalene acetic acid .
Molecular weight : 230.26

Mechanism of Action :

Nonsteroidal anti- inflammatory drugs ( NSAIDs ) inhibit the activity of the enzyme cyclo – oxygenase, resulting in decreased formation of precursors of prostaglandins and thromboxanes from arachidonic acid . (USPDI 2005)

Pharmacokinetics :

Naproxen is rapidly and completely absorbed from the gastrointestinal tract with an in vivo bioavailability of 95% . The elimination half life naproxen is 12 to 17 hours. After administration of Naproxen tablets, peak plasma levels are attained in 2 to 4 hours. Naproxen has a volume of distribution of 0.16 L/kg .
At therapeutic levels naproxen is greater than 99% albumin – bound . Naproxen is extensively metabolized in the liver to 6-o-desmethyl naproxen , and both parent and metabolites do not induce metabolizing enzymes.
Approximately 95% of naproxen from any does is excreted in the urine . Peak plasma levels are attained in 2 to 4 hours . ( PDR 2007 )

Indications :

Rheumatoid arthritis, Osteoarthritis , Ankylosing spondylitis, Juvenile arthritis, Relief of mild to moderate pain, Acute gouty arthritis, Bursitis Tendonitis, Fever, Dysmenorrhea, Vascular headaches. ( USPDI 2005 )

Contraindications :

Naproxen is contraindicated in patients with known hypersensitivity to it. Also , it should not be given to patients who have experienced asthma, urticaria, or allergic type reactions after taking aspirin or other NSAIDs . Sever , rarely fatal anaphylactic – like reactions to NSAIDs. have been reported in such patients . Naproxen is contraindicated for the treatment of peri- operative pain in the setting of coronary artery bypass graft ( CABG ) surgery. ( PDR 2007 )

Warnings :

  • - Cardiovascular effects
  • - Cardiovascular thrombotic events :
    Patients with known cardiovascular disease or risk factors for cardiovascular disease may be at greater risk of serious cadiovascular thrombotic events, myocardial infarction and stroke, so the lowest effective dose should be used for the shortest duration possible . Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. (PDR 2007)
  • - Hypertension :
    Blood pressure should be monitored closely during the initiation of NSAIDs treatment and throughout the course of therapy. (PDR 2007)
  • - Gastrointestinal Effects :
    Serious gastrointestinal adverse events such as bleeding , ulceration and perforation can occur at any time, with or without warning symptoms, in patients treated chronically with NSAIDs. ( PDR 2007 )
  • - Renal Effects :
    Long – term administration of NSAIDs has resulted in renal papillary necrosis and renal injury. Close monitoring of the patient's renal function in patients with advanced renal disease is advisable. (PDR 2007 )
  • - Anaphylactoid Reactions :
    Anaphylactoid - Reactions may occur in patients without known prior exposure to naproxen. Naproxen should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps , or who exhibit sever, potentially fatal bronchospasm after taking aspirin or other NSAIDs . Emergency help should be sought in cases where an anaphylactoid reaction occurs. (PDR 2007)
  • - Skin Reactions :
    Naproxen can cause serious skin adverse events such as exfoliative dermatitis, Steven – Johnson Syndrom ( SJS) , and toxic epidermal necrolysis (TEN) , which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity. ( PDR 2007 )
  • -Pregnancy :
    In late pregnancy , as with other NSAIDs , naproxen should be avoided because it may cause premature closures of the ductus arteriosus. (PDR 2007 )
  • - Nursing mothers :
    Because of the possible adverse effects of prostaglandin- inhibiting drugs on neonates use in nursing mothers should be avoided . ( PDR 2007 )
  • -Pediatrics:
    Studies in children 2 years of age and older with juvenile arthritis have shown higher incidence of naproxen - induced skin rash and increase bleeding time as compared with adults. Studies in children younger than 2 years of age have not been done. (USPDI 2005 )
  • - Geriatrics :
    Studies have shown that the unbound ( Free ) Fraction of naproxen, but not the total plasma concentration , may be increased in geriatric patients. The steady state concentration of unbound naproxen may be almost doubled in patients as compared with younger adults. (USPDI 2005 )

Precautions :

Naproxen – containing products should not be used concomitantly since they all circulate in the plasma as the naproxen anion.
Naproxen cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency . Abrupt discontinuation of corticosteroids may lead to disease exacerbation . Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids , the patient should be observed closely for any evidence of adverse effects, including adrenal insufficiency and exacerbation of symptoms of arthritis.
Patients with initial hemoglobin values of 10 grams or less who are to receive long – term therapy should have hemoglobin values determined periodically .
Because of adverse eye findings in animal studies with drugs of this class, it is recommended that ophthalmic studies be carried out if any change or disturbance in vision occurs . ( PDR 2007 ) .

Hepatic effects :

Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs . The SGPT ( ALT ) test is probably the most sensitive indicator of liver dysfunction . A patient with symptoms and/or signs suggesting liver dysfunction , or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of more severe hepatic reaction while on therapy with naproxen . Chronic alcoholic liver disease and probably other disease with decreased or abnormal plasma proteins(albumin) reduce the total plasma concentration of naproxen , but the plasma concentration of unbound naproxen, is increased.Some adjustment of dosage may be required in these patients. (PDR 2007 )

Hematological Effects :

Patients on long – term treatment with NSAIDs , including naproxen should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia.
NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients.Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration and reversible . Patients receiving naproxen may be adversely affected by alterations in platelet function , such as those with coagulation disorders or patient receiving anticoagulants should be carefully monitored. ( PDR 2007)

Preexisting Asthma :

Patients with asthma may have aspirin–sensitive asthma. In such aspirin – sensitive patients , naproxen should not be administered to them, and should be used with caution in patients with preexisting asthma.

Drug Interactions:

ACE – inhibitors :
NSAIDs may diminish the antihypertensive effect of ACE – inhibitors. (USPDI 2005 )

Acetaminophen :

Prolonged concurrent use of acetaminophen with an NSAID may increase the risk of adverse renal effects, it is recommended that patients be under close medical supervision while receiving such combined therapy. (USPDI 2005)
Alcohol, Corticosteroids, Glucocorticoid or corticotropin ( Chronic therapeutic use ) or potassium supplements .
Concurrent use with an NSAID may increase the risk of gastrointestinal side effects, including ulceration or hemorrhage, however , concurrent use with a glucocorticoid or corticotropin in the treatment of arthritis may provide additional therapeutic benefit and permit reduction of glucocorticoid or corticotropin dosage . )
Anticoagulants coumarine – or indanedione – derivative or Heparin or Thrombolytic agents:
Coagulation tests should be monitored and anticoagulant dosage adjustments made, if necessary , when NSAID therapy is initiated or discontinued . ( USPDI 2005 )

Antidiabetic agents :

NSAIDS may increase the hypoglycemic effect of these medications because prostaglandins are directly involved in regulatory mechanisms of glucose metabolism and possibly because of displacement of the oral anti diabetics from serum proteins; dosage adjustment of the antidiabetic agent may be necessary ; glipizide and glyburide, due to their nonionic binding characteristics, may not be affected as much as the other oral antidiabetic agents; however , caution with concurrent use is recommended . ( USPDI 2005)

Antihypertensives or Diuretics, especially triamterene :

Increased monitoring of the response to an antihypertensives or diuretics may be advisable, because naproxen has been shown to reduce or reverse the effects of antihypertensives, possibly by inhibiting renal prostaglandin synthesis.
Concurrent use of an NSAID and a diuretic may increase the risk of renal failure secondary to decrease in renal blood flow caused by inhibition of renal prostaglandin synthesis. (USPDI 2005)

Aspirin or NSAIDS :

Concurrent use of two or more NSAIDs , including aspirin, is not recommended , concurrent therapy may increase the risk of gastrointestinal toxicity , including ulceration or hemorrhage, without providing additional symptomatic relief. ( USPDI 2005) .
Also concurrent administration of two or more NSAIDs may after the pharmacokinetic profile of at least one of the medications which may alter the therapeutic effect and / or increase the risk of adverse effects.

Bone marrow depressant :

Dosage adjustment of the bone marrow depressant, if necessary, should be based on blood counts. (USPDI 2005)

Colchicine :

Inhibition of platelet aggregation by NSAIDs added to colchicine's effects on blood clotting mechanisms [ colchicine may cause thrombocytopenia with chronic use and clotting defects,including disseminated intravascular coagulation with over dose ] may increase the risk of bleeding at sites other than the gastrointestinal tract. (USPDI 2005)

Cyclosporine or Gold compounds or Nephrotoxic medications :

Inhibition of renal prostaglandin activity by NSAIDs may increase the plasma concentration of cyclosporine and/ or the risk of cyclosporine – induced nephrotoxicity ; patients should be carefully monitored during concurrent use.
The risk of adverse renal effects may also be increased when an NSAID is used concurrently with other nephrotoxic medications , possibly including gold compounds [ although NSAIDs and gold compounds are commonly used concurrently in the treatment of arthritis ] . (USPDI 2005)

Lithium :

Naproxen have been reported to increase the steady state concentration of lithium, possibly by decreasing its renal clearance ; increased monitoring of lithium concentration is recommended during and following concurrent use. ( USPDI 2005)

Methotrexate :

NSAIDs may decrease protein binding and / or renal elimination of methotrexate, resulting in increased and prolonged methotrexate plasma concentrations and an increased risk of toxicity , especially during high – dose methotrexate infusions.
NSAID therapy should not be resumed following the infusion until the methotrexate plasma concentration has decreased to a nontoxic level, usually at least 12 hours.
Severe, sometimes fatal, methotrexate toxicity has also been reported when NSAIDs were used concurrently with low to moderate doses of methotrexate, including doses commonly used in the treatment of rheumatoid arthritis or psoriasis; caution in concurrent use is recommended, with dosage of methotrexate being adjusted as determined by monitoring the plasma methotrexate concentration and / or adequacy of the patient's renal function . ( USPDI 2005)

Photosensitizing medications, other :

Concurrent use with photosensitizing NSAIDs my cause additive photosensitizing effects. (USPDI 2005)

Platelet aggregation inhibitors, , sulfinpyrazone :

Concurrent use with an NSAID may increase the risk of bleeding because of additive inhibition of platelet aggregation , as well as the potential for NSAID – induced gastrointestinal ulceration or hemorrhage. ( USPDI 2005 )

Probenecid :

Probenecid has been shown to increase plasma concentrations of naproxen, leading to increased risk of toxicity and possibly to increased effectiveness of NSAID; if concurrent use is necessary, it is recommended that naproxen be administered in reduced dosage . (USPDI 2005)

Laboratory value alterations :

5 – HIAA, urine , determinations
( naproxen may interfere with some assays )
Steroid , urine, determinations
( 17 – ketogenic steroid concentrations may be falsely increased by naproxen when m–dinitrobenzene reagent is used ; although 17 – hydroxy corticosteroid measurements are not significantly altered when the Porter – Silber test is used, naproxen therapy should be discontinued 72 hours before adrenal function tests are performed ) (USPDI 2005 )

Side effects :

  • • Gastrointestinal : constipation , heart burn, abdominal pain, nausea, diarrhea, dyspepsia, stomatitis .
  • • Central Nervous System : headache , dizziness , drowsiness lightheadedness , vertigo .
  • • Dermatologic : pruritus (itching ) , skin eruptions , echymoses, sweating, purpura .
  • • Special Senses : tinnitus, visual disturbances , hearing disturbances
  • • Cardiovascular : edema, palpitations
  • • General : dyspnea, thirst .

Over dosage :

Significant naproxen over dosage may by characterized by lethargy . dizziness, drowsiness, epigastric pain, abdominal discomfort , heartburn , indigestion, nausea, transient alterations in liver function, hypoprothrombinemia, renal dysfunction, metabolic acidosis, apnea, disorientation or vomiting . Gastrointestinal bleeding can occur.
Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs and may occur following an overdose. There are no specific antidotes . Hemodialysis does not decrease the plasma concentration of naproxen because of the high degree of its protein binding . Emesis and/ or activated charcoal ( 60 to 100 g in adults, 1 to 2 g/kg in children ) and/ or osmotic cathartic may be indicated in patients seen within 4 hours of ingestion with symptoms or following a large over dose . Forced diuresis, alkanization of urine or hemoperfusion may not be useful due to high protein binding. ( PDR 2007)

Dosage and administration :

A lower dose should be considered in patients with renal or hepatic impairment or in elderly patients (PDR 2007 )

Usual adult dose :

Usual adult dose : Antirheumatic : ( nonsteroidal anti – inflammatory )
Oral , 250 , 375 , or 500 mg two times a day, morning and evening . Note : During long – term administration, dosage may be adjusted according to patient response ; lower doses may suffice. For acute exacerbations of rheumatic disease, dosage may be increased to up to 1.5 grams per day for limited periods . Use of this high dose requires that the clinical benefit be increased sufficiently to offset the potential increased risk of adverse effects.
Anti – inflammatory ( nonsteroidal ) or Analgesic ( mild to moderate pain ) or Antidysmenorrhea :
Oral , 500 mg initially , then 250 mg every six to eight hours as needed . ( USPDI 2005 )
Antigout agent :
Oral, 750 mg initially, the 250 mg every eight hours until the attack has subsided. ( USPDI 2005 )
Usual adult prescribing limits :
For mild to moderate pain and dysmenorrhea up to a total dose of 1.25 grams daily . ( USPDI 2005 )
Usual pediatric dose :
Antirheumatic ( nonsteroidal anti – inflammatory ) Oral, 10 mg per kg of body weight per day, given in two divided doses . ( USPDI 2005)

Packaging and Storage :

Store between 15 and 30°c in a well – closed container. ( USPDI 2005 )

How Supplied :

Naproxen 250 mg is light green, scored, round tablet.There are blisters of 10's , box of 100's

References :

USPDI 2005 , PDR 2007
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