WARNINGS
Cardiovascular Effects
Cardiovascular Thrombotic Events
Clinical trials of several COX-2 selective and nonselective
NSAIDs of up to three years duration have shown an increased risk of serious
cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which
can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a
similar risk. Patients with known CV disease or risk factors for CV disease may
be at greater risk. To minimize the potential risk for an adverse CV event in
patients treated with an NSAID, 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.
Patients should be informed about the signs and/or symptoms of serious CV events
and the steps to take if they occur.
There is no consistent evidence that concurrent use of aspirin mitigates the
increased risk of serious CV thrombotic events associated with NSAID use. The
concurrent use of aspirin and an NSAID does increase the risk of serious GI
events (see WARNINGS, Gastrointestinal
Effects - Risk of Ulceration, Bleeding, and Perforation).
Two large, controlled clinical trials of a COX-2 selective NSAID for the
treatment of pain in the first 10 to 14 days following CABG surgery found an
increased incidence of myocardial infarction and stroke (see CONTRAINDICATIONS).
Hypertension
NSAIDs, including etodolac capsules, can lead to onset of new
hypertension or worsening of preexisting hypertension, either of which may
contribute to the increased incidence of CV events. Patients taking thiazides or
loop diuretics may have impaired response to these therapies when taking NSAIDs.
NSAIDs, including etodolac capsules, should be used with caution in patients
with hypertension. Blood pressure (BP) should be monitored closely during the
initiation of NSAID treatment and throughout the course of therapy.
Congestive Heart Failure and Edema
Fluid retention and edema have been observed in some patients
taking NSAIDs. Etodolac capsules should be used with caution in patients with
fluid retention or heart failure.
Gastrointestinal Effects – Risk of Ulceration, Bleeding, and
Perforation
NSAIDs, including etodolac capsules, can cause serious
gastrointestinal (GI) adverse events including inflammation, bleeding,
ulceration, and perforation of the stomach, small intestine, or large intestine,
which can be fatal. These serious adverse events can occur at any time, with or
without warning symptoms, in patients treated with NSAIDs. Only one in five
patients, who develop a serious upper GI adverse event on NSAID therapy, is
symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs
occur in approximately 1% of patients treated for 3 to 6 months, and in about 2
to 4% of patients treated for one year. These trends continue with longer
duration of use, increasing the likelihood of developing a serious GI event at
some time during the course of therapy. However, even short-term therapy is not
without risk. Physicians should inform patients about the signs and/or symptoms
of serious GI toxicity and what steps to take if they occur.
NSAIDs should be prescribed with extreme caution in those with a prior
history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease, and/or
gastrointestinal bleeding, and who use NSAIDs have a greater than 10 fold
increased risk for developing a GI bleed compared to patients with neither of
these risk factors. Other factors that increase the risk for GI bleeding in
patients treated with NSAIDs include concomitant use of oral corticosteroids or
anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older
age, and poor general health status. Most spontaneous reports of fatal GI events
are in elderly or debilitated patients and therefore, special care should be
taken in treating this population.
To minimize the potential risk for an adverse GI event in patients treated
with an NSAID, the lowest effective dose should be used for the shortest
possible duration. Patients and physicians should remain alert for signs and
symptoms of GI ulceration and bleeding during NSAID therapy and promptly
initiate additional evaluation and treatment if a serious GI adverse event is
suspected. This should include discontinuation of the NSAID until a serious GI
adverse event is ruled out. For high risk patients, alternate therapies that do
not involve NSAIDs should be considered.
Renal Effects
Long-term administration of NSAIDs has resulted in renal
papillary necrosis and other renal injury. Renal toxicity has also been seen in
patients in whom renal prostaglandins have a compensatory role in the
maintenance of renal perfusion. In these patients, administration of a
non-steroidal anti-inflammatory drug may cause a dose-dependent reduction in
prostaglandin formation and, secondarily, in renal blood flow, 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 ACE-inhibitors, and the elderly.
Discontinuation of NSAID therapy is usually followed by recovery to the
pretreatment state.
Renal pelvic transitional epithelial hyperplasia, a spontaneous change
occurring with variable frequency, was observed with increased frequency in
treated male rats in a 2 year chronic study.
Advanced Renal Disease
No information is available from controlled clinical studies
regarding the use of etodolac capsules in patients with advanced renal disease.
Therefore, treatment with etodolac capsules is not recommended in these patients
with advanced renal disease. If etodolac capsule therapy must be initiated,
close monitoring of the patient's renal function is advisable.
Anaphylactoid Reactions
As with other NSAIDs, anaphylactoid reactions may occur in
patients without prior exposure to etodolac capsules. Etodolac capsules 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 severe, potentially fatal bronchospasm after taking
aspirin or other NSAIDs. Fatal reactions have been reported in such patients
(see CONTRAINDICATIONS and PRECAUTIONS, General,
Preexisting Asthma). Emergency help should be sought in cases where an
anaphylactoid reaction occurs.
Skin Reactions
NSAIDs, including etodolac capsules, can cause serious skin
adverse events such as exfoliative dermatitis, Stevens-Johnson syndrome (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.
Pregnancy
In late pregnancy, the third trimester, as with other NSAIDs,
etodolac capsules should be avoided because they may cause premature closure of
the ductus arteriosus (see PRECAUTIONS, Pregnancy,
Nonteratogenic Effects).
PRecautions
General
Etodolac capsules 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 pharmacological activity of etodolac capsules in reducing fever and
inflammation may diminish the utility of these diagnostic signs in detecting
complications of presumed noninfectious, painful conditions.
Hepatic Effects
Borderline elevations of one or more liver tests may occur in up
to 15% of patients taking NSAIDs including etodolac capsules. These laboratory
abnormalities may progress, may remain unchanged, or may be transient with
continuing therapy. Notable elevations of ALT or AST (approximately three or
more times the upper limit of normal) have been reported in approximately 1% of
patients in clinical trials with NSAIDs. In addition, rare cases of severe
hepatic reactions, including jaundice and fatal fulminant hepatitis, liver
necrosis, and hepatic failure, some of them with fatal outcomes, have been
reported.
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 etodolac
capsules. If clinical signs and symptoms consistent with liver disease develop,
or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), etodolac
capsules should be discontinued.
Hematological Effects
Anemia is sometimes seen in patients receiving NSAIDs, including
etodolac capsules. This may be due to fluid retention, occult or gross GI blood
loss, or an incompletely described effect upon erythropoiesis. Patients on
long-term treatment with NSAIDs, including etodolac capsules, 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
etodolac capsules who may be adversely affected by alterations in platelet
function, such as those with coagulation disorders or patients receiving
anticoagulants, should be carefully monitored.
Preexisting Asthma
Patients with asthma may have aspirin-sensitive asthma. The use
of aspirin in patients with aspirin-sensitive asthma has been associated with
severe bronchospasm which can be fatal. Since cross reactivity, including
bronchospasm, between aspirin and other non-steroidal anti-inflammatory drugs
has been reported in such aspirin-sensitive patients, etodolac capsules should
not be administered to patients with this form of aspirin sensitivity and should
be used with caution in patients with preexisting asthma.
Information for Patients
Patients should be informed of the following
information before initiating therapy with an NSAID and periodically during the
course of ongoing therapy. Patients should also be encouraged to read the NSAID
Medication Guide that accompanies each prescription dispensed.
- Etodolac capsules, like other NSAIDS, may cause serious CV side effects,
such as MI or stroke, which may result in hospitalization and even death.
Although serious CV events can occur without warning symptoms, patients should
be alert for the signs and symptoms of chest pain, shortness of breath,
weakness, slurring of speech, and should ask for medical advice when observing
any indicative signs or symptoms. Patients should be apprised of the importance
of this follow-up (see WARNINGS, Cardiovascular
Effects).
- Etodolac capsules, like other NSAIDs, can cause GI discomfort and, rarely,
serious GI side effects, such as ulcers and bleeding, which may result in
hospitalization and even death. Although serious GI tract ulcerations and
bleeding can occur without warning symptoms, patients should be alert for the
signs and symptoms of ulcerations and bleeding, and should ask for medical
advice when observing any indicative signs or symptoms including epigastric
pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the
importance of this follow-up (see WARNINGS, Gastrointestinal
Effects - Risk of Ulceration, Bleeding, and Perforation).
- Etodolac capsules, like other NSAIDs, can cause serious skin side effects
such as exfoliative dermatitis, SJS, and TEN, which may result in
hospitalization and even death. Although serious skin reactions may occur
without warning, patients should be alert for the signs and symptoms of skin
rash and blisters, fever, or other signs of hypersensitivity such as itching,
and should ask for medical advice when observing any indicative signs or
symptoms. Patients should be advised to stop the drug immediately if they
develop any type of rash and contact their physicians as soon as possible.
- Patients should promptly report signs or symptoms of unexplained weight gain
or edema to their physicians.
- Patients should be informed of the warning signs and symptoms of
hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper
quadrant tenderness, and “flu-like” symptoms). If these occur, patients should
be instructed to stop the therapy and seek immediate medical therapy.
- Patients should be informed of the signs of an anaphylactoid reaction (e.g.,
difficulty breathing, swelling of the face or throat). If these occur, patients
should be instructed to seek immediate emergency help (see WARNINGS).
- In late pregnancy, the third trimester, as with other NSAIDs, etodolac
capsules should be avoided because they may cause premature closure of the
ductus arteriosus.
Laboratory Tests
Because serious GI tract ulcerations and bleeding can occur
without warning symptoms, physicians should monitor for signs or symptoms of GI
bleeding. Patients on long-term treatment with NSAIDs, should have their CBC and
a chemistry profile checked periodically for signs or symptoms of anemia.
Appropriate measures should be taken in case such signs of anemia occur. If
clinical signs and symptoms consistent with liver or renal disease develop,
systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if abnormal
liver tests persist or worsen, etodolac capsules should be discontinued.
Drug Interactions
ACE-inhibitors
Reports suggest that NSAIDs may diminish the antihypertensive
effect of ACE-inhibitors. This interaction should be given consideration in
patients taking NSAIDs concomitantly with ACE-inhibitors (see WARNINGS).
Antacids
The concomitant administration of antacids has no apparent effect
on the extent of absorption of etodolac. However, antacids can decrease the peak
concentration reached by 15% to 20% but have no detectable effect on the
time-to-peak.
Aspirin
When etodolac is administered with aspirin, its protein binding
is reduced, although the clearance of free etodolac is not altered. The clinical
significance of this interaction is not known; however, as with other NSAIDs,
concomitant administration of etodolac and aspirin is not generally recommended
because of the potential of increased adverse effects.
Cyclosporine, Digoxin, Methotrexate
Etodolac, like other NSAIDs, through effects on renal
prostaglandins, may cause changes in the elimination of these drugs leading to
elevated serum levels of cyclosporine, digoxin, methotrexate, and increase
toxicity. Nephrotoxicity associated with cyclosporine may also be enhanced.
Patients receiving these drugs who are given etodolac, or any other NSAID, and
particularly those patients with altered renal function, should be observed for
the development of the specific toxicities of these drugs. NSAIDs have been
reported to competitively inhibit methotrexate accumulation in rabbit kidney
slices. This may indicate that they could enhance the toxicity of methotrexate.
Caution should be used when NSAIDs are administered concomitantly with
methotrexate.
Diuretics
Etodolac has no apparent pharmacokinetic interaction when
administered with furosemide or hydrochlorothiazide. Nevertheless, clinical
studies, as well as post marketing observations have shown that etodolac can
reduce the natriuretic effect of furosemide and thiazides in some patients. This
response has been attributed to inhibition of renal prostaglandin synthesis.
During concomitant therapy with NSAIDs, the patient should be observed closely
for sings of renal failure (see WARNINGS, Renal
Effects), as well as to assure diuretic efficacy.
Glyburide
Etodolac has no apparent pharmacokinetic interaction when
administered with glyburide.
Lithium
NSAIDs have produced an elevation of plasma lithium levels and a
reduction in renal lithium clearance. The mean minimum lithium concentration
increased 15% and the renal clearance was decreased by approximately 20%. These
effects have been attributed to inhibition of renal prostaglandin synthesis by
the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects
should be observed carefully for signs of lithium toxicity.
Phenylbutazone
Phenylbutazone causes increase (by about 80%) in the free
fraction of etodolac. Although in vivo studies have
not been done to see if etodolac clearance is changed by coadministration of
phylbutazone, it is not recommended that they be coadministered.
Phenytoin
Etodolac has no apparent pharmacokinetic interaction when
administered with phenytoin.
Warfarin
The effects of warfarin and NSAIDs on GI bleeding are
synergistic, such that users of both drugs together have a risk of serious GI
bleeding higher than that of users of either drug alone. Short-term
pharmacokinetic studies have demonstrated that concomitant administration of
warfarin and etodolac results in reduced protein binding of warfarin, but there
was no change in the clearance of free warfarin. There was no significant
difference in the pharmacodynamic effect of warfarin administered alone and
warfarin administered with etodolac as measured by prothrombin time. Thus,
concomitant therapy with warfarin and etodolac should not require dosage
adjustment of either drug. However, caution should be exercised because there
have been a few spontaneous reports of prolonged prothrombin times, with or
without bleeding, in etodolac-treated patients receiving concomitant warfarin
therapy.
Drug/Laboratory Test Interactions
The urine of patients who take etodolac can give a false-positive
reaction for urinary bilirubin (urobilin) due to the presence of phenolic
metabolites of etodolac. Diagnostic dip-stick methodology, used to detect ketone
bodies in urine, has resulted in false-positive findings in some patients
treated with etodolac. Generally, this phenomenon has not been associated with
other clinically significant events. No dose relationship has been observed.
Etodolac treatment is associated with a small decrease in serum uric acid
levels. In clinical trials, mean decreases of 1 to 2 mg/dL were observed in
arthritic patients receiving etodolac (600 mg to 1000 mg/day) after 4 weeks of
therapy. These levels then remained stable for up to 1 year of therapy.
Carcinogenesis, Mutagenesis, Impairment of
Fertility
No carcinogenic effect of etodolac was observed in mice or rats
receiving oral doses of 15 mg/kg/day (45 to 89 mg/m2,
respectively) or less for periods of 2 years or 18 months, respectively.
Etodolac was not mutagenic in in vitro tests
performed with S. typhimurium and mouse lymphoma
cells as well as in an in vivo mouse micronucleus
test. However, data from the in
vitro human peripheral lymphocyte test showed an increase
in the number of gaps (3.0 to 5.3% unstained regions in the chromatid without
dislocation) among the etodolac-treated cultures (50 to 200 mcg/mL) compared to
negative controls (2.0%); no other difference was noted between the controls and
drug-treated groups. Etodolac showed no impairment of fertility in male and
female rats up to oral doses of 16 mg/kg (94 mg/m2).
However, reduced implantation of fertilized eggs occurred in the 8 mg/kg
group.
Pregnancy
Teratogenic Effects
Pregnancy category C
In teratology studies, isolated occurrences of alterations in
limb development were found and included polydactyly, oligodactyly, syndactyly,
and unossified phalanges in rats and oligodactyly and synostosis of metatarsals
in rabbits. These were observed at dose levels (2 to 14 mg/kg/day) close to
human clinical doses. However, the frequency and the dosage group distribution
of these findings in initial or repeated studies did not establish a clear drug
or dose-response relationship. Animal reproduction studies are not always
predictive of human response. There are no adequate and well-controlled studies
in pregnant women. Etodolac should be used in pregnancy only if the potential
benefit justifies the potential risk to the fetus.
Nonteratogenic Effects
Etodolac should be used during pregnancy only if the potential
benefits justify the potential risk to the fetus. Because of the known effects
of non-steroidal anti-inflammatory drugs on the fetal cardiovascular system
(closure of ductus arteriosus), use during pregnancy (particularly during the
third trimester) should be avoided.
Labor and Delivery
In rat studies with NSAIDs, as with other drugs known to inhibit
prostaglandin synthesis, an increased incidence of dystocia, delayed
parturition, and decreased pup survival occurred. The effects of etodolac on
labor and delivery in pregnant women are unknown.
Nursing Mothers
It is not known whether etodolac is excreted in human milk.
Because many drugs are excreted in human milk and because of the potential for
serious adverse reactions in nursing infants from etodolac, a decision should be
made whether to discontinue nursing or to discontinue the drug taking into
account the importance of the drug to the mother.
Pediatric Use
Safety and effectiveness in pediatric patients below the age of
18 years have not been established.
Geriatric Use
As with any NSAIDs, caution should be exercised in treating the
elderly (65 years and older) and when increasing the dose (see WARNINGS).
In etodolac clinical studies, no overall differences in safety or
effectiveness were observed between these patients and younger patients. In
pharmacokinetic studies, age was shown not to have any effect on etodolac
half-life or protein binding, and there was no change in expected drug
accumulation. Therefore, no dosage adjustment is generally necessary in the
elderly on the basis of pharmacokinetics (see CLINICAL
PHARMACOLOGY, Special Populations).
Elderly patients may be more sensitive to the antiprostaglandin effects of
NSAIDs (on the gastrointestinal tract and kidneys) than younger patients (see
WARNINGS). In particular, elderly or debilitated
patients who receive NSAID therapy seem to tolerate gastrointestinal ulceration
or bleeding less well than other individuals, and most spontaneous reports of
fatal GI events are in this population.
Etodolac is eliminated primarily by the kidney. Because elderly patients are
more likely to have decreased renal function, care should be taken in dose
selection, and it may be useful to monitor renal function (see WARNINGS, Renal Effects).
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