WARNINGS AND PRECAUTIONS
Cardiovascular ThromboticEvents
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.
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
].
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 and
Precautions
].
Gastrointestinal(GI) Effects – Risk of GI Ulceration, Bleeding, and Perforation
NSAIDs, including MOBIC, 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.
Prescribe
NSAIDs, including MOBIC, 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
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, use the lowest effective dose for
the shortest possible duration. Patients and physicians should remain
alert for signs and symptoms of GI ulceration and bleeding during
MOBIC therapy and promptly initiate additional evaluation and treatment
if a serious GI adverse event is suspected. This should include discontinuation
of MOBIC until a serious GI adverse event is ruled out. For high-risk
patients, consider alternate therapies that do not involve NSAIDs.
Hepatic Effects
Borderline elevations of one or more liver
tests may occur in up to 15% of patients taking NSAIDs including MOBIC.
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
[
see Adverse Reactions
].
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 MOBIC. If clinical signs and symptoms consistent
with liver disease develop, or if systemic manifestations occur (e.g.,
eosinophilia, rash, etc.), discontinue MOBIC [
see
Use in Specific Populations and
Clinical Pharmacology
].
Hypertension
NSAIDs, including MOBIC, can lead to onset
of new hypertension or worsening of pre-existing hypertension, either
of which may contribute to the increased incidence of CV events. NSAIDs,
including MOBIC, 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.
Patients taking ACE inhibitors, thiazides,
or loop diuretics may have impaired response to these therapies when
taking NSAIDs.
Congestive HeartFailure and Edema
Fluid
retention and edema have been observed in some patients taking NSAIDs.
Use MOBIC with caution in patients with fluid retention, hypertension,
or heart failure.
Renal Effects
Long-term administration of NSAIDs, including
MOBIC, can result in renal papillary necrosis, renal insufficiency,
acute renal failure, 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 nonsteroidal 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, ACE-inhibitors,
and angiotensin II receptor antagonists, and the elderly. Discontinuation
of NSAID therapy is usually followed by recovery to the pretreatment
state.
A pharmacokinetic study
in patients with mild and moderate renal impairment revealed that
no dosage adjustments in these patient populations are required. Patients
with severe renal impairment have not been studied. The use of MOBIC
in patients with severe renal impairment with CrCl less than 20 mL/min
is not recommended. A study performed in patients on hemodialysis
revealed that although overall Cmax was diminished
in this population, the proportion of free drug not bound to plasma
was increased. Therefore it is recommended that meloxicam dosage in
this population not exceed 7.5 mg per day. Closely monitor the renal
function of patients with impaired renal function who are taking MOBIC
[
see Dosage and Administration , Use in Specific Populations , and Clinical Pharmacology
].
Use caution when initiating treatment with MOBIC in patients with
considerable dehydration. It is advisable to rehydrate patients first
and then start therapy with MOBIC. Caution is also recommended in
patients with pre-existing kidney disease.
The extent to which metabolites may accumulate in patients
with renal impairment has not been studied with MOBIC. Because some
MOBIC metabolites are excreted by the kidney, monitor patients with
significant renal impairment closely.
Anaphylactoid Reactions
As with other NSAIDs, anaphylactoid reactions
have occurred in patients without known prior exposure to MOBIC. MOBIC
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 [
see Contraindications and Warnings
and Precautions
]. Seek emergency help in cases where an anaphylactoid reaction
occurs.
Adverse Skin Reactions
NSAIDs, including MOBIC, 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. Inform patients
about the signs and symptoms of serious skin manifestations and discontinue
use of the drug at the first appearance of skin rash or any other
sign of hypersensitivity.
Pregnancy
Starting at 30 weeks gestation, avoid the
use of MOBIC because it may cause premature closure of the ductus
arteriosus [
see Use in Specific Populations and Patient Counseling Information
].
CorticosteroidTreatment
MOBIC cannot
be expected to substitute for corticosteroids or to treat corticosteroid
insufficiency. Abrupt discontinuation of corticosteroids may lead
to disease exacerbation. Slowly taper patients on prolonged corticosteroid
therapy if a decision is made to discontinue corticosteroids.
Masking of Inflammationand Fever
The pharmacological
activity of MOBIC in reducing fever and inflammation may diminish
the utility of these diagnostic signs in detecting complications of
presumed noninfectious, painful conditions.
Hematological Effects
Anemia may occur in patients receiving NSAIDs,
including MOBIC. 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 MOBIC, 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. Carefully
monitor patients treated with MOBIC who may be adversely affected
by alterations in platelet function, such as those with coagulation
disorders or patients receiving anticoagulants.
Use in Patientswith Pre-existing 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 NSAIDs has been
reported in such aspirin-sensitive patients, MOBIC should not be administered
to patients with this form of aspirin sensitivity and should be used
with caution in patients with pre-existing asthma.
Monitoring
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. 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, MOBIC should
be discontinued.
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category C;
Category D starting 30 weeks gestation
There are no adequate and well-controlled
studies in pregnant women. Meloxicam crosses the placental barrier.
Prior to 30 weeks gestation, use MOBIC during pregnancy only if the
potential benefit justifies the potential risk to the fetus. Starting
at 30 weeks gestation, avoid MOBIC and other NSAIDs, in pregnant women
as premature closure of the ductus arteriosus in the fetus may occur.
If this drug is used during this time period in pregnancy, inform
the patient of the potential hazard to a fetus [
see Warnings and Precautions and Patient Counseling Information
].
Teratogenic Effects
Meloxicam was not
teratogenic when administered to pregnant rats during fetal organogenesis
at oral doses up to 4 mg/kg/day (2.6-fold greater than the maximum
recommended human daily dose [MRHD] based on body surface area [BSA]
comparison). Administration of meloxicam to pregnant rabbits throughout
embryogenesis produced an increased incidence of septal defects of
the heart at an oral dose of 60 mg/kg/day. The no effect level was
20 mg/kg/day (26-fold greater than the MRHD based on BSA conversion).
Nonteratogenic Effects
In rats and rabbits,
embryolethality occurred at oral meloxicam doses of 1 mg/kg/day and
5 mg/kg/day, respectively (0.65- and 6.5-fold greater, respectively,
than the MRHD based on BSA comparison) when administered throughout
organogenesis.
Labor and Delivery
The effects of MOBIC on labor and delivery of pregnant women are
unknown. Oral administration of meloxicam to pregnant rats during
late gestation through lactation increased the incidence of dystocia,
delayed parturition, and decreased offspring survival at meloxicam
doses of 0.125 mg/kg/day or greater (at least 12.5 times lower than
the maximum recommended human daily dose based on body surface area
comparison).
Nursing Mothers
It is not known whether this drug is excreted in human milk; however,
meloxicam was excreted in the milk of lactating rats at concentrations
higher than those in plasma. Because many drugs are excreted in human
milk and because of the potential for serious adverse reactions in
nursing infants from MOBIC, 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
The safety and effectiveness of meloxicam in pediatric JRA patients
from 2 to 17 years of age has been evaluated in three clinical trials
[
see Dosage and Administration , Adverse Reactions , and Clinical Studies
].
Geriatric Use
As with any NSAID, caution should be exercised in treating the elderly
(65 years and older).
Of the
total number of subjects in clinical studies, 5157 were age 65 and
over (4044 in OA studies and 1113 in RA studies). No overall differences
in safety or effectiveness were observed between these subjects and
younger subjects, and other reported clinical experience has not identified
differences in responses between the elderly and younger patients,
but greater sensitivity of some older individuals cannot be ruled
out.
Hepatic Impairment
No dose adjustment is necessary in patients
with mild to moderate hepatic impairment. Patients with severe hepatic
impairment have not been adequately studied. Since meloxicam is significantly
metabolized in the liver; the use of meloxicam in these patients should
be done with caution [
see Warnings and Precautions and Clinical Pharmacology
].
Renal Impairment
No dose adjustment is necessary in patients
with mild to moderate renal impairment. Patients with severe renal
impairment have not been studied. The use of MOBIC in subjects with
severe renal impairment is not recommended. Following a single dose
of meloxicam, the free Cmax plasma concentrations
were higher in patients with renal failure on chronic hemodialysis
(1% free fraction) in comparison to healthy volunteers (0.3% free
fraction). Therefore, it is recommended that meloxicam dosage in this
population not exceed 7.5 mg per day. Hemodialysis did not lower the
total drug concentration in plasma; therefore, additional doses are
not necessary after hemodialysis. Meloxicam is not dialyzable [
see Dosage and Administration , Warnings and Precautions , and Clinical Pharmacology
].
Females of Reproductive Potential
Data from several small studies in humans and from
studies in animals indicate that NSAIDs, including MOBIC, may be associated
with a reversible delay in ovulation. Therefore, in women who have
difficulties conceiving, or who are undergoing investigation of infertility,
use of meloxicam is not recommended.
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