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
Ansaid Warnings, Precautions, Pregnancy, Nursing, Abuse - Flurbiprofen
Ansaid Warnings, Precautions, Pregnancy, Nursing, Abuse - Flurbiprofen
WARNINGS
Risk of Gastrointestinal (GI) Ulceration's, Bleeding and Perforation
with Nonsteroidal Anti-inflammatory 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 nonsteroidal anti-inflammatory
drugs. Although minor
upper GI problems, such
as dyspepsia, are
common, usually developing early in therapy,
physicians should remain alert for ulceration and bleeding
in patients treated chronically with nonsteroidal anti-inflammatory
drugs, even in the absence
of previous GI tract
symptoms. In patients observed
in clinical trials
of such agents for several
months to two years, 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 nonsteroidal anti-inflammatory
agents in causing such
reactions. High doses of any such
agent 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.
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 the patients of the importance of this follow-up.
PRECAUTIONS
General
Impaired Renal or Hepatic Function: As with other
nonsteroidal anti-inflammatory drugs, flurbiprofen should be used
with caution in patients with impaired renal
or hepatic function,
or a history of kidney
or liver disease. Studies to assess the pharmacokinetics
of flurbiprofen in patients with decreased liver
function have not been
done.
Renal Effects: Toxicology studies in rats have shown
renal papillary necrosis
at dosage levels equivalent
on a mg/kg basis to those
used clinically in humans. Similar findings were seen in monkeys
given high doses (50-100 mg/kg, or approximately 20-40 times the
human therapeutic dose)
for 90 days.
In clinical studies,
kidney function
tests were done at least monthly in patients taking flurbiprofen.
In these studies, renal
effects of flurbiprofen were similar to those seen with other nonsteroidal
anti-inflammatory
drugs.
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
prostaglandin's 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, which 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
drug therapy
is typically followed by recovery
to the pretreatment
state. Those patients at high risk who chronically take
flurbiprofen should have renal
function monitored
if they have signs or symptoms that may be consistent with mild
azotemia, such as malaise,
fatigue, loss
of appetite, etc.. Occasional patients may develop some elevation
of serum creatinine
and BUN levels without signs
or symptoms.
The elimination
half-life of flurbiprofen
was unchanged in patients with end
stage renal
disease (ESRD). Flurbiprofen
metabolites are primarily eliminated by the kidneys and elimination
of 4’ -hydroxy-flurbiprofen was markedly reduced in E.R.
patients. Therefore, patients with significantly impaired renal
function may require
a reduction of dosage
to avoid accumulation of flurbiprofen metabolites and should be
monitored (See also the CLINICAL
PHARMACOLOGY section).
Liver Tests: As
with other nonsteroidal anti-inflammatory drugs, border
line 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 disappear with continued
therapy. The ALT (SGPT)
test is probably the most sensitive
indicator of liver
injury. Meaningful (3 times the upper limit
of normal) elevations of ALT
or AST (SGOT) have been
reported 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 a more severe hepatic
reaction while on therapy
with flurbiprofen
Anemia: Anemia is commonly observed in rheumatoid
arthritis and is sometimes aggravated by nonsteroidal anti-inflammatory
drugs, which may produce fluid
retention or minor
gastrointestinal
blood loss
in some patients Therefore, patients who have initial
hemoglobin values
of 10 g/dL or less, and who are to receive long-term therapy,
should have hemoglobin values determined periodically.
Fluid Retention and Edema: Fluid retention
and edema have been reported,
therefore, flurbiprofen should be used with caution in patients
with cardiac decompensation.
hypertension, or
similar conditions.
Vision Changes: Blurred and or diminished vision
has been reported with the use of flurbiprofen and other non-steroidal
anti-inflammatory drugs. Patients experiencing eye
complaints should have ophthalmologic examinations.
Effect on Platelets and Coagulation: Flurbiprofen
inhibits collagen-induced platelet
aggregation. Prolongation of bleeding
time by flurbiprofen has
been demonstrated in humans after single and multiple oral doses.
Patients who may be adversely affected by prolonged bleeding time
should be carefully observed when flurbiprofen is administered.
Information for Patients
See PATIENT INFORMATION
section.
Drug Interactions
See DRUG INTERACTIONS
section.
Carcinogenesis Mutagenesis, Impairment of Fertility
An 80-week study in mice at doses of 2, 5, and 12 mg/kg/day and
a 2-year study in rats at doses of 0.5, 2, and 4 mg/kg/day did not
show evidence of carcinogenicity
at maximum tolerated
doses of flurbiprofen.
Flurbiprofen did not impair the fertility
of male or female
rats treated orally at 2.25 mg/kg/day for 65 days and 16 days, respectively,
before mating.
Pregnancy
Teratogenic Effects: Pregnancy Category B: In
teratology studies
flurbiprofen given to mice in doses up to 12 mg/kg/day to rats in
doses up to 25 mg/kg/day, and to rabbits in doses up to 7 5 mg/kg/day
showed no teratogenic
effects.
Because there are no adequate
and well-controlled studies in pregnant women, and animal
teratology studies
do not always predict human
response, flurbiprofen is not recommended for use in pregnancy.
Labor and Delivery
Flurbiprofen's effects on labor
and delivery in women are not known. As
with other drugs known to inhibit prostaglandin synthesis, an increased
incidence of dystocia
and delayed parturition
occurred in rats treated throughout pregnancy. Because of the known
effects of prostaglandin inhibiting drugs on the fetal
cardiovascular
system (closure of the
ductus arteriosus), use of flurbiprofen during late pregnancy
is not recommended.
Nursing Mothers
Concentrations of flurbiprofen in breast
milk and plasma of nursing
mothers suggested that a nursing
infant could receive
approximately 0.10 mg flurbiprofen
per day in the established
milk of a woman taking
200 mg/day. Because of possible adverse effects of prostaglandin-inhibiting
drugs on neonates, flurbiprofen is not recommended for use in nursing
mothers.
Pediatric Use
Safety and effectiveness
in pediatric patients
have not been established.
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