CONTRAINDICATIONS
The drug is contraindicated in patients who have had allergic reactions to naproxen. It is also
contraindicated in patients in whom aspirin or other nonsteroidal anti-inflammatory/analgesic drugs
induce the syndrome of asthma, rhinitis, and nasal polyps. Both types of reactions have the potential
of being fatal. Anaphylactoid reactions to naproxen whether of the true allergic type ot the
pharmacologic idiosyncratic (e.g., aspirin syndrome) type, usually but not always occur in patients
with a known history of such reactions. Therefore, careful questioning of patients for such things as
asthma, nasal polyps, urticaria, and hypotension associated with nonsteroidal anti-inflammatory
drugs before starting therapy is important. In addition, if such symptoms occur during therapy,
treatment should be discontinued.
WARNINGS
Risk of GI Ulceration, Bleeding and Perforation with NSAID Therapy
Serious gastrointestinal toxicity such as bleeding, ulceration, and perforation, can occur at any time,
with or without warning symptoms, in patients treated chronically with NSAID therapy. Although
minor upper gastrointestinal problems, such as dyspepsia, are common, usually developing early in
therapy, physicians should remain alert for ulceration and bleeding in patients treated chronically
with NSAIDs even in the absence of previous GI tract symptoms. In patients observed in clinical
trials of several months to two years duration, symptomatic upper GI ulcers, gross bleeding or
perforation appear to occur in approximately 1% of patients treated for 3-6 months, and in about
2-4% of patients treated for one year. Physicians should inform patients about the signs and/or
symptoms of serious GI toxicity and what steps to take if they occur.
Studies to date have not identified any subset of patients not at risk of developing peptic ulceration
and bleeding. Except for a prior history of serious GI events and other risk factors known to be
associated with peptic ulcer disease, such as alcoholism, smoking, etc., no risk factors (e.g., age,
sex) have been associated with increased risk. Elderly or debilitated patients seem to tolerate
ulceration or bleeding less well than other individuals and most spontaneous reports of fatal GI
events are in this population. Studies to date are inconclusive concerning the relative risk of various
NSAIDs in causing such reactions. High doses of any NSAID probably carry a greater risk of
these reactions, although controlled clinical trials showing this do not exist in most cases. In
considering the use of relatively large doses (within the recommended dosage range), sufficient
benefit should be anticipated to offset the potential increased risk of GI toxicity.
PRECAUTIONS
General
NAPROXEN SHOULD NOT BE USED CONCOMITANTLY WITH THE RELATED
DRUG ANAPROX OR ANAPROX DS (NAPROXEN SODIUM) SINCE THEY BOTH
CIRCULATE IN PLASMA AS THE NAPROXEN ANION.
Renal Effects: As with other nonsteroidal anti-inflammatory drugs, long-term administration of
naproxen to animals has resulted in renal papillary necrosis and other abnormal renal pathology. In
humans, there have been reports of acute interstitial nephritis with hematuria, proteinuria, and
occasionally nephrotic syndrome.
A second form of renal toxicity has been seen in patients with prerenal conditions leading to a
reduction in renal blood flow or blood volume, where the renal prostaglandins have a supportive role
in the maintenance of renal perfusion. In these patients, administration of a nonsteroidal
anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and may
precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with
impaired renal function, heart failure, liver dysfunction, those taking diuretics, and the elderly.
Discontinuation of nonsteroidal anti-inflammatory therapy is typically followed by recovery to the
pretreatment state.
Naproxen and its metabolites are eliminated primarily by the kidneys, therefore, the drug should be
used with great caution in patients with significantly impaired renal function and the monitoring of
serum creatinine and/or creatinine clearance is advised in these patients. Caution should be used if
the drug is given to patients with creatinine clearance of less than 20 ml/minute because
accumulation of naproxen metabolites has been seen in patients.
Chronic alcoholic liver disease and probably other forms of cirrhosis reduce the total plasma
concentration of naproxen, but the plasma concentration of unbound naproxen is increased. It is
prudent to use the lowest effective dose.
One study indicates that, although total plasma concentration of naproxen is unchanged, the
unbound plasma fraction of naproxen is increased in the elderly. As with other drugs used in the
elderly, it is prudent to use the lowest effective dose.
As with other nonsteroidal anti-inflammatory drugs, borderline elevations of one or more liver tests
may occur in up to 15% of patients. These abnormalities may progress, may remain essentially
unchanged, or may be transient with continued therapy. The SGPT (ALT) test is probably the most
sensitive indicator of liver dysfunction. Meaningful (3 times the upper limit of normal) elevations of
SGPT or SGOT (AST) occurred in controlled clinical trials in less than 1% of patients. 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 this drug. Severe hepatic reactions, including jaundice and cases of fatal
hepatitis, have been reported with this drug as with other nonsteroidal anti-inflammatory drugs.
Although such reactions are rare, if abnormal liver tests persist or worsen, if clinical signs and
symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g.,
eosinophilia, rash, etc.), this drug should be discontinued.
If steroid dosage is reduced or eliminated during therapy, the steroid dosage should be reduced
slowly and the patients must 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.
Peripheral edema has been observed in some patients. For this reason, the drug should be used with
caution in patients with retention, hypertension or heart failure.
Naproxen suspension contains 8 mg/ml of sodium. This should be considered in patients whose
overall intake of sodium must be restricted.
The antipyretic and anti-inflammatory activities of the drug may reduce fever and inflammation,
thus diminishing their utility as diagnostic signs in detecting complications of presumed
non-infectious, non-inflammatory painful conditions.
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.
Information for the Patient
Naproxen, like other drugs of its class, is not free of side effects. The side effects of these drugs
can cause discomfort and, rarely, there are more serious side effects, such as gastrointestinal
bleeding, which may result in hospitalization and even fatal outcomes.
NSAIDs (Nonsteroidal Anti-Inflammatory Drugs) are often essential agents in the management of
arthritis and have a major role in the treatment of pain, but they also may be commonly employed
for conditions which are less serious.
Physicians may wish to discuss with their patients the potential risks (see WARNINGS and
ADVERSE REACTIONS) and likely benefits of NSAID treatment, particularly when the drugs
are used for less serious conditions where treatment without NSAIDs may represent an acceptable
alternative to both the patient and physician.
Caution should be exercised by patients whose activities require alertness if they experience
drowsiness, dizziness, vertigo or depression during therapy with the drug.
Laboratory Tests
Because serious GI tract ulceration and bleeding can occur without warning symptoms, physicians
should follow chronically treated patients for the signs and symptoms of ulceration and bleeding and
should inform them of the importance of this follow-up (see WARNINGS, Risk of GI Ulceration,
Bleeding and Perforation with NSAID Therapy.)
Drug/Laboratory Test Interactions
The drug may decrease platelet aggregation and prolong bleeding time. This effect should be kept in
mind when bleeding times are determined.
The administration of the drug may result in increased urinary values for 17-ketogenic steroids
because of an interaction between the drug and/or its metabolites with m-dinitrobenzene used in this
assay. Although 17 hydroxy-corticosteroid measurements (Porter-Silber test) do not appear to be
artifactually altered, it is suggested that therapy with the drug be temporarily discontinued 72 hours
before adrenal function tests are performed.
The drug may interfere with some urinary assays of 5-hydroxy indoleacetic acid (5HIAA).
Carcinogenesis
A two-year study was performed in rats to evaluate the carcinogenic potential of the drug. No
evidence of carcinogenicity was found.
Pregnancy Category B
Teratogenic Effects: Reproduction studies have been performed in rats, rabbits, and mice at doses
up to 6 times the human dose and have revealed no evidence of impaired fertility or harm to the
fetus due to the drug. There are, however, no adequate and well-controlled studies in pregnant
women. Because animal reproduction studies are not always predictive of human response, the
drug should not be used during pregnancy unless clearly needed. Because of the known effect of
drugs of this class on the human fetal cardiovascular system (closure of ductus arteriosus), use
during late pregnancy should be avoided.
Nonteratogenic Effects: As with other drugs known to inhibit prostaglandin synthesis, an increased
incidence of dystocia and delayed parturition occurred in rats.
Nursing Mothers
The naproxen anion has been found in the milk of lactating women at a concentration of
approximately 1% of that found in the plasma. Because of the possible adverse effects of
prostaglandin-inhibiting drugs on neonates, use in nursing mothers should be avoided.
Pediatric Use
Safety and effectiveness in children below the age of 2 years have not been established. Pediatric
dosing recommendations for juvenile arthritis are based on well-controlled studies (See DOSAGE
AND ADMINISTRATION.) There are no adequate effectiveness or dose-response data for other
pediatric conditions, but the experience in juvenile arthritis and other use experience have
established that single doses of 2.5-5 mg/kg, with a total daily dose not exceeding 15 mg/kg/day, are
safe in children over 2 years of age.