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
Anaprox Warnings, Precautions, Pregnancy, Nursing, Abuse - Naproxen Sodium
Anaprox Warnings, Precautions, Pregnancy, Nursing, Abuse - Naproxen Sodium
WARNINGS
Risk Of Gi Ulceration,
Bleeding And Perforation With Nsaid
Therapy
Serious GI 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 GI problems, such
as dyspepsia, are
common, usually developing early in therapy,
physicians should remain alert for ulcerations and bleeding
in patients treated chronically with NSAIDs
even in the absence of previous GI
tract symptoms. In
patients observed in clinical
trials with naproxen 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 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 (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
NAPRELAN SHOULD NOT BE USED CONCOMITANTLY WITH OTHER NAPROXEN
PRODUCTS SINCE THEY ALL
CIRCULATE IN THE PLASMA AS
THE NAPROXEN ANION.
The antipyretic
and anti-inflammatory activities of the drug
may reduce fever
and inflammation,
thus diminishing their utility as diagnostic
signs.
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 NSAIDs, 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
NSAIDs. In patients with
prerenal conditions
with reduction in
renal blood
flow or blood
volume, renal prostaglandins have a supportive role
in the maintenance of renal perfusion. Administration of a NSAID
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,
diuretic use, and the
elderly. Discontinuation of NSAID
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 has been seen
in such patients.
Hepatic Effects
As with other NSAIDs, 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 resolve
with continued therapy. The ALT
(SGPT) is probably the most sensitive indicator
of liver dysfunction.
Meaningful (3 times the upper limit of normal) elevations of ALT
(SGPT) or AST (SGOT) 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 NSAIDs. 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, fever,
etc.), naproxen should be discontinued. 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.
Fluid Retention and Edema
Peripheral edema has
been observed in some patients receiving naproxen. Naprelan (naproxen
sodium) tablets contain 37.5 mg
or 50 mg of sodium
(1.5 mEq or 2.0 mEq
respectively). This should be considered in patients whose overall
intake of sodium
must be severely restricted. For these reasons, Naprelan should
be used with caution in patients with fluid
retention, hypertension
or heart failure.
Information For Patients
Naprelan, like other drugs of its class, is not free of side
effects. This formulation of naproxen can cause
discomfort and rarely,
there are more serious side
effects, such as GI bleeding,
which may result in hospitalization
and even fatal outcomes. NSAIDs
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 w.s. to discuss with
their patients the potential
risks (see WARNINGS
and ADVERSE
REACTIONS) and likely benefits of Naprelan treatment.
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 Naprelan for the 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.
Patients with initial
hemoglobin values
of 10 grams or less who are to receive long-term therapy
should have hemoglobin
values determined periodically. (See WARNINGS
—RISK
OF GI ULCERATION, BLEEDING AND PERFORATION WITH NSAID
THERAPY).
Drug Interactions
See DRUG INTERACTIONS
section.
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-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 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 two year study was performed in rats to evaluate the carcinogenic
potential of naproxen
at doses of 8 mg/kg/day, 16 mg/kg/day, and 24 mg/kg/day (50 mg/m2,
100 mg/m2, and 150 mg/m2). 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/m2/day, 0.23
times the human systemic
exposure) rabbits at 20 mg/kg/day (220 mg/m2/day, 0.27
times the human systemic
exposure) and mice at 170 mg/kg/day (510 mg/m2/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, Naprelan should be used during pregnancy
only if the potential
benefits justify the potential
risks to the fetus.
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 the 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 the plasma. Because of the
possible adverse effects of prostaglandin-inhibiting drugs on neonates,
use in nursing mothers
should be avoided.
Pediatric Use
No pediatric studies
have been performed with Naprelan, thus safety of Naprelan in pediatric
populations has not been established.
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