A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Naprosyn Warnings, Precautions, Pregnancy, Nursing, Abuse - Naproxen
Naprosyn Warnings, Precautions, Pregnancy, Nursing, Abuse - Naproxen
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 2 years’ duration, symptomatic upper
GI ulcers, gross bleeding or perforation appear to occur in approximately 1%
of patients treated for 3 to 6 months and in about 2% to 4% of patients treated
for 1 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 with all naproxen products have not identified any subset of
patients not at risk of developing peptic ulceration and bleeding or any differences
between different naproxen products in their propensity to cause 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 ( eg, 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- CONTAINING PRODUCTS SUCH AS NAPROSYN, EC- NAPROSYN,
ANAPROX, ANAPROX DS, NAPROSYN SUSPENSION, ALEVE ® * , AND OTHER NAPROXEN
PRODUCTS SHOULD NOT BE USED CONCOMITANTLY SINCE THEY ALL CIRCULATE IN THE PLASMA
AS THE NAPROXEN ANION.
If the steroid dose is reduced or eliminated during therapy, the steroid dosage
should be reduced slowly and 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.
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 noninfectious, noninflammatory 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.
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, hematuria, proteinuria and occasionally
nephrotic syndrome associated with naproxen- containing products and other NSAIDs
since they have been marketed.
A second form of renal toxicity has been seen in patients taking naproxen as
well as other nonsteroidal antiinflammatory drugs. 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, administration of a nonsteroidal anti- inflammatory drug may cause
a dose- dependent reduction in prostaglandin formation and 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 antiinflammatory 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 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 such patients.
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.
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.
Studies indicate that although total plasma concentration of naproxen is unchanged,
the unbound plasma fraction of naproxen is increased in the elderly. 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.
Hepatic Function: 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 naproxen. Severe hepatic reactions, including jaundice
and cases of fatal hepatitis, have been reported with naproxen 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 ( eg, eosinophilia,
rash, etc.), naproxen should be discontinued.
Fluid Retention and Edema: Peripheral edema has been observed
in some patients receiving naproxen. Since each ANAPROX or ANAPROX DS tablet
contains 25 mg or 50 mg of sodium ( about 1 mEq per each 250 mg of naproxen),
and each teaspoonful of NAPROSYN Suspension contains 39 mg ( about 1.5 mEq per
each 125 mg of naproxen) of sodium, this should be considered in patients whose
overall intake of sodium must be severely restricted. For these reasons, ANAPROX,
ANAPROX DS and NAPROSYN Suspension should be used with caution in patients with
fluid retention, hypertension or heart failure.
Information for Patients: Naproxen, in NAPROSYN, EC- NAPROSYN,
ANAPROX, ANAPROX DS and NAPROSYN Suspension, like other drugs of this class,
is not free of side effects. The side effects of these formulations of naproxen
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 that are less serious.
Physicians may wish to discuss with their patients the potential risks ( see
WARNINGS
, PRECAUTIONS
and ADVERSE REACTIONS)
and likely benefits of naproxen treatment, particularly when it is 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 naproxen.
Laboratory Tests: Because serious GI tract ulceration and bleeding
can occur without warning symptoms, physicians should follow patients chronically
treated with naproxen for signs and symptoms of ulceration and bleeding and
should inform them of the importance of this follow- up and what they should
do if certain signs and symptoms do appear ( see WARNINGS
:
Risk of GI Ulcerations, Bleeding and Perforation With NSAID Therapy ).
Drug Interactions: The use of NSAIDs in patients who are receiving
ACE inhibitors may potentiate renal disease states ( see PRECAUTIONS
:
Renal Effects ).
In vitro studies have shown that naproxen anion, because of its affinity for
protein, may displace from their binding sites other drugs that are also albumin-
bound ( see CLINICAL PHARMACOLOGY:
Pharmacokinetics ).
Theoretically, the naproxen anion itself could likewise be displaced. Short-
term controlled studies failed to show that taking the drug significantly affects
prothrombin times when administered to individuals on coumarin- type anticoagulants.
Caution is advised nonetheless, since interactions have been seen with other
nonsteroidal agents of this class. Similarly, patients receiving the drug and
a hydantoin, sulfonamide or sulfonylurea should be observed for signs of toxicity
to these drugs ( see CLINICAL STUDIES:
General Information ).
Concomitant administration of naproxen and aspirin is not recommended because
naproxen is displaced from its binding sites during the concomitant administration
of aspirin, resulting in lower plasma concentrations and peak plasma levels.
The natriuretic effect of furosemide has been reported to be inhibited by some
drugs of this class. Inhibition of renal lithium clearance leading to increases
in plasma lithium concentrations has also been reported. Naproxen and other
nonsteroidal anti- inflammatory drugs can reduce the antihypertensive effect
of propranolol and other betablockers.
Probenecid given concurrently increases naproxen anion plasma levels and extends
its plasma half- life significantly.
Caution should be used if naproxen is administered concomitantly with methotrexate.
Naproxen, naproxen sodium and other nonsteroidal anti- inflammatory drugs have
been reported to reduce the tubular secretion of methotrexate in an animal model,
possibly increasing the toxicity of methotrexate.
Due to the gastric pH elevating effects of H 2 - blockers, sucralfate and intensive
antacid therapy, concomitant administration of EC- NAPROSYN is not recommended.
Drug/ Laboratory Test Interactions: Naproxen may decrease platelet
aggregation and prolong bleeding time. This effect should be kept in mind when
bleeding times are determined.
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. Although 17- hydroxycorticosteroid
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.
Naproxen may interfere with some urinary assays of 5- hydroxy indoleacetic
acid ( 5HIAA).
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 ( 50, 100, and 150 mg/ m 2 ). The maximum dose used was 0.28 times the systemic
exposure to humans at the recommended dose. No evidence of tumorigenicity was
found.
Pregnancy: Teratogenic Effects: Pregnancy Category B
. Reproduction studies have been performed in rats at 20 mg/ kg/ day ( 125
mg/ m 2 / day, 0.23 times the human systemic exposure), rabbits at 20 mg/ kg/
day ( 220 mg/ m 2 / day, 0.27 times the human systemic exposure), and mice at
170 mg/ kg/ day ( 510 mg/ m 2 / day, 0.28 times the human systemic exposure)
with no evidence of impaired fertility or harm to the fetus due to the drug.
There are no adequate and well- controlled studies in pregnant women. Because
animal reproduction studies are not always predictive of human response, naproxen
should not be used during pregnancy unless clearly needed.
Nonteratogenic Effects: 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 effect of drugs of this class on the human fetal
cardiovascular system ( closure of ductus arteriosus), use during third trimester
should be avoided.
Nursing Mothers: The naproxen anion has been found in the milk
of lactating women at a concentration of approximately 1% of that found in 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 pediatric patients
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 to 5 mg/
kg ( as naproxen suspension, see DOSAGE AND
ADMINISTRATION), with total daily dose not exceeding 15 mg/ kg/ day,
are well tolerated in pediatric patients over 2 years of age.
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