Included as part of the PRECAUTIONS section.
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, including myocardial
infarction (MI) and stroke, which can be fatal. Based on available data, it is
unclear that the risk for CV thrombotic events is similar for all NSAIDs. The
relative increase in serious CV thrombotic events over baseline conferred by
NSAID use appears to be similar in those with and without known CV disease or risk
factors for CV disease. However, patients with known CV disease or risk factors
had a higher absolute incidence of excess serious CV thrombotic events, due to
their increased baseline rate. Some observational studies found that this
increased risk of serious CV thrombotic events began as early as the first
weeks of treatment. The increase in CV thrombotic risk has been observed most
consistently at higher doses.
To minimize the potential risk for an adverse CV event in
NSAID-treated patients, use the lowest effective dose for the shortest duration
possible. Physicians and patients should remain alert for the development of
such events, throughout the entire treatment course, even in the absence of
previous CV symptoms. Patients should be informed about the 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, such as meloxicam,
increases the risk of serious gastrointestinal (GI) events [see Gastrointestinal Bleeding, Ulceration, and Perforation].
Status Post Coronary Artery Bypass Graft (CABG) Surgery
Two large, controlled clinical trials of a COX-2
selective NSAID for the treatment of pain in the first 10–14 days following
CABG surgery found an increased incidence of myocardial infarction and stroke.
NSAIDs are contraindicated in the setting of CABG [see CONTRAINDICATIONS].
Observational studies conducted in the Danish National
Registry have demonstrated that patients treated with NSAIDs in the post-MI
period were at increased risk of reinfarction, CV-related death, and all-cause
mortality beginning in the first week of treatment. In this same cohort, the
incidence of death in the first year post-MI was 20 per 100 person years in
NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed
patients. Although the absolute rate of death declined somewhat after the first
year post-MI, the increased relative risk of death in NSAID users persisted
over at least the next four years of follow-up.
Avoid the use of VIVLODEX in patients with a recent MI
unless the benefits are expected to outweigh the risk of recurrent CV
thrombotic events. If VIVLODEX is used in patients with a recent MI, monitor
patients for signs of cardiac ischemia.
Gastrointestinal Bleeding, Ulceration, And Perforation
NSAIDs, including meloxicam, cause serious
gastrointestinal (GI) adverse events including inflammation, bleeding,
ulceration, and perforation of the esophagus, 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 VIVLODEX.
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 occurred in approximately 1% of patients treated for 3-6 months, and
in about 2%-4% of patients treated for one year. However, even short-term NSAID
therapy is not without risk.
Risk Factors for GI Bleeding, Ulceration, and Perforation
Patients with a prior history of peptic ulcer disease
and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk
for developing a GI bleed compared to patients without these risk factors.
Other factors that increase the risk for GI bleeding in patients treated with
NSAIDs include longer duration of NSAID therapy; concomitant use of oral
corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake
inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health
status. Most postmarketing reports of fatal GI events occurred in elderly or
debilitated patients. Additionally, patients with advanced liver disease and/or
coagulopathy are at increased risk for GI bleeding.
Strategies to Minimize the GI Risks in NSAID-treated
- Use the lowest effective dosage for the shortest possible
- Avoid administration of more than one NSAID at a time.
- Avoid use in patients at higher risk unless benefits are
expected to outweigh the increased risk of bleeding. For high risk patients, as
well as those with active GI bleeding, consider alternate therapies other than
- Remain alert for signs and symptoms of GI ulceration and
bleeding during NSAID therapy.
- If a serious GI adverse event is suspected, promptly
initiate evaluation and treatment, and discontinue VIVLODEX until a serious GI
adverse event is ruled out.
- In the setting of concomitant use of low-dose aspirin for
cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding
[see DRUG INTERACTIONS].
Elevations of ALT or AST (three or more times the upper
limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated
patients in clinical trials. In addition, rare, sometimes fatal, cases of
severe hepatic injury, including fulminant hepatitis, liver necrosis, and
hepatic failure have been reported.
Elevations of ALT or AST (less than three times ULN) may
occur in up to 15% of patients treated with NSAIDs including meloxicam.
Inform patients of the warning signs and symptoms of
hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice,
right upper quadrant tenderness, and “flulike” symptoms). If clinical
signs and symptoms consistent with liver disease develop, or if systemic
manifestations occur (e.g., eosinophilia, rash, etc.), discontinue VIVLODEX
immediately, and perform a clinical evaluation of the patient.
NSAIDs, including VIVLODEX, can lead to new onset or
worsening of pre-existing hypertension, either of which may contribute to the
increased incidence of CV events. Patients taking angiotensin converting enzyme
(ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired
response to these therapies when taking NSAIDs [see DRUG INTERACTIONS].
Monitor blood pressure (BP) during the initiation of
NSAID treatment and throughout the course of therapy.
Heart Failure And Edema
The Coxib and traditional NSAID Trialists' Collaboration
meta-analysis of randomized controlled trials demonstrated an approximately
two-fold increase in hospitalizations for heart failure in COX-2
selective-treated patients and nonselective NSAID-treated patients compared to
placebo-treated patients. In a Danish National Registry study of patients with
heart failure, NSAID use increased the risk of MI, hospitalization for heart
failure, and death.
Additionally, fluid retention and edema have been
observed in some patients treated with NSAIDs. Use of meloxicam may blunt the
CV effects of several therapeutic agents used to treat these medical conditions
(e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see
Avoid the use of VIVLODEX in patients with severe heart
failure unless the benefits are expected to outweigh the risk of worsening
heart failure. If VIVLODEX is used in patients with severe heart failure,
monitor patients for signs of worsening heart failure.
Renal Toxicity And Hyperkalemia
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 an NSAID 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, dehydration, hypovolemia, heart failure, liver
dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the
elderly. Discontinuation of NSAID therapy was usually followed by recovery to
the pretreatment state.
No information is available from controlled clinical
studies regarding the use of VIVLODEX in patients with advanced renal disease.
The renal effects of VIVLODEX may hasten the progression of renal dysfunction
in patients with pre-existing renal disease.
Correct volume status in dehydrated or hypovolemic
patients prior to initiating VIVLODEX. Monitor renal function in patients with
renal or hepatic impairment, heart failure, dehydration, or hypovolemia during
use of VIVLODEX [see DRUG INTERACTIONS]. Avoid the use of VIVLODEX in
patients with advanced renal disease unless the benefits are expected to
outweigh the risk of worsening renal function. If VIVLODEX is used in patients
with advanced renal disease, monitor patients for signs of worsening renal
Increases in serum potassium concentration, including
hyperkalemia, have been reported with use of NSAIDs, even in some patients
without renal impairment. In patients with normal renal function, these effects
have been attributed to a hyporeninemic-hypoaldosteronism state.
Meloxicam has been associated with anaphylactic reactions
in patients with and without known hypersensitivity to meloxicam and in
patients with aspirin-sensitive asthma [see CONTRAINDICATIONS, Exacerbation of Asthma Related to Aspirin Sensitivity below].
Seek emergency help if an anaphylactic reaction occurs.
Exacerbation Of Asthma Related To Aspirin Sensitivity
A subpopulation of patients with asthma may have aspirin-sensitive
asthma which may include chronic rhinosinusitis complicated by nasal polyps;
severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other
NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been
reported in such aspirin-sensitive patients, VIVLODEX is contraindicated in
patients with this form of aspirin sensitivity [see CONTRAINDICATIONS].
When VIVLODEX is used in patients with preexisting asthma (without known
aspirin sensitivity), monitor patients for changes in the signs and symptoms of
Serious Skin Reactions
NSAIDs, including meloxicam, can cause serious skin
adverse reactions 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 reactions, and to discontinue the use of VIVLODEX at the first
appearance of skin rash or any other sign of hypersensitivity. VIVLODEX is
contraindicated in patients with previous serious skin reactions to NSAIDs [see
Premature Closure Of Fetal Ductus Arteriosus
Meloxicam may cause premature closure of the fetal ductus
arteriosus. Avoid use of NSAIDs, including VIVLODEX, in pregnant women starting
at 30 weeks of gestation (third trimester) [see Use in Specific Populations].
Anemia has occurred in NSAID-treated patients. This may
be due to occult or gross blood loss, fluid retention, or an incompletely
described effect upon erythropoiesis. If a patient treated with VIVLODEX has
any signs or symptoms of anemia, monitor hemoglobin or hematocrit.
NSAIDs, including VIVLODEX, may increase the risk of
bleeding events. Concomitant use of warfarin and other anticoagulants,
antiplatelet agents (e.g., aspirin), and serotonin reuptake inhibitors (SSRIs)
and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this
risk. Monitor these patients for signs of bleeding [see DRUG INTERACTIONS].
Masking Of Inflammation And Fever
The pharmacological activity of VIVLODEX in reducing
inflammation, and possibly fever, may diminish the utility of diagnostic signs
in detecting infections.
Because serious GI bleeding, hepatotoxicity, and renal
injury can occur without warning symptoms or signs, consider monitoring
patients on long-term NSAID treatment with a CBC and a chemistry profile
Patient Counseling Information
Advise the patient to read the
FDA-approved patient labeling (Medication Guide) that accompanies each
prescription dispensed. Patients, families, or their caregivers should be
informed of the following information before initiating therapy with VIVLODEX
and periodically during the course of ongoing therapy.
Advise patients to be alert for
the symptoms of cardiovascular thrombotic events, including chest pain,
shortness of breath, weakness, or slurring of speech, and to report any of
these symptoms to their health care provider immediately [see WARNINGS AND
Gastrointestinal Bleeding, Ulceration, and Perforation
Advise patients to report symptoms of ulcerations and
bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to
their health care provider. In the setting of concomitant use of low-dose
aspirin for cardiac prophylaxis, inform patients of the increased risk for and
the signs and symptoms of GI bleeding [see WARNINGS
Inform patients of the warning signs and symptoms of
hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice,
right upper quadrant tenderness, and “flu-like” symptoms). If these occur,
instruct patients to stop VIVLODEX and seek immediate medical therapy [see WARNINGS AND PRECAUTIONS].
Heart Failure and Edema
Advise patients to be alert for the symptoms of
congestive heart failure including shortness of breath, unexplained weight
gain, or edema and to contact their healthcare provider if such symptoms occur
[see WARNINGS AND PRECAUTIONS].
Inform patients of the signs of an anaphylactic reaction
(e.g., difficulty breathing, swelling of the face or throat). Instruct patients
to seek immediate emergency help if these occur [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS].
Serious Skin Reactions
Advise patients to stop VIVLODEX immediately if they
develop any type of rash and to contact their healthcare provider as soon as
possible [see WARNINGS AND PRECAUTIONS].
Inform pregnant women to avoid use of VIVLODEX and other
NSAIDs starting at 30 weeks gestation because of the risk of the premature
closing of the fetal ductus arteriosus [see WARNINGS
AND PRECAUTIONS, Use In Specific Populations].
Avoid Concomitant Use of NSAIDs
Inform patients that the concomitant use of VIVLODEX with
other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended
due to the increased risk of gastrointestinal toxicity, and little or no
increase in efficacy [see WARNINGS AND PRECAUTIONS,
DRUG INTERACTIONS]. Alert patients that NSAIDs may be present in “over
the counter” medications for treatment of colds, fever, or insomnia.
Use of NSAIDs and Low-Dose Aspirin
Inform patients not to use low-dose aspirin concomitantly
with VIVLODEX until they talk to their healthcare provider [see DRUG
Carcinogenesis, Mutagenesis, And Impairment Of Fertility
There was no increase in tumor incidence in long-term
carcinogenicity studies in rats (104 weeks) and mice (99 weeks) administered
meloxicam at oral doses up to 0.8 mg/kg/day in rats and up to 8.0 mg/kg/day in
mice (up to 0.8- and 3.9-times, respectively, the maximum recommended daily
dose (MRDD) of 10 mg of VIVLODEX based on body surface area (BSA) comparison).
Meloxicam was not mutagenic in an Ames assay, or
clastogenic in a chromosome aberration assay with human lymphocytes and an in
vivo micronucleus test in mouse bone marrow.
Impairment of Fertility
In previous studies of meloxicam, there was no impairment
of male or female fertility in rats at oral doses up to 9 mg/kg/day in males
and 5 mg/kg/day in females (up to 8.7 and 4.8-times, respectively, the MRDD
based on BSA comparison).
Use In Specific Populations
Use of NSAIDs, including
VIVLODEX, during the third trimester of pregnancy increases the risk of
premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs,
including VIVLODEX, in pregnant women starting at 30 weeks of gestation (third
There are no adequate and
well-controlled studies of VIVLODEX in pregnant women. Data from observational
studies regarding potential embryofetal risks of NSAID use in women in the
first or second trimesters of pregnancy are inconclusive. In the general U.S.
population, all clinically recognized pregnancies, regardless of drug exposure,
have a background rate of 2-4% for major malformations, and 15-20% for
In animal reproduction studies, embryofetal death was
observed in rats and rabbits treated during the period of organogenesis with
meloxicam at oral doses equivalent 1- and 10-times, respectively, the maximum
recommended daily dose (MRDD) of VIVLODEX. Increased incidence of septal heart
defects were observed in rabbits treated throughout embryogenesis with
meloxicam at an oral dose equivalent to 116-times the MRDD. In pre-and
post-natal reproduction studies, increased incidence of dystocia, delayed
parturition, and decreased offspring survival were observed in rats treated
with meloxicam at an oral dose equivalent to 0.12-times the MRDD of VIVLODEX.
No teratogenic effects were observed in rats treated with meloxicam during
organogenesis at an oral dose equivalent to 3.9- times the MRDD [See Data].
Based on animal data, prostaglandins have been shown to
have an important role in endometrial vascular permeability, blastocyst
implantation, and decidualization. In animal studies, administration of
prostaglandin synthesis inhibitors such as meloxicam, resulted in increased
pre- and post-implantation loss.
Labor or Delivery
There are no studies on the effects of VIVLODEX during
labor or delivery. In animal studies, NSAIDs, including meloxicam, inhibit
prostaglandin synthesis, cause delayed parturition, and increase the incidence
Meloxicam was not teratogenic when administered to
pregnant rats during fetal organogenesis at oral doses up to 4 mg/kg/day (3.9-times
the maximum recommended daily dose (MRDD) of 10 mg of VIVLODEX 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 (116-times the MRDD based on BSA
comparison). The no effect level was 20 mg/kg/day (39-times the MRDD based on
BSA comparison). In rats and rabbits, embryolethality occurred at oral
meloxicam doses of 1 mg/kg/day and 5 mg/kg/day, respectively (1- and 10-times
the MRDD based on BSA comparison) when administered throughout organogenesis.
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 (0.12-times the MRDD based on BSA comparison).
There are no human data available on whether meloxicam is
present in human milk, or on the effects on breastfed infants, or on milk
production. The developmental and health benefits of breastfeeding should be
considered along with the mother's clinical need for VIVLODEX and any potential
adverse effects on the breastfed infant from the VIVLODEX or from the
underlying maternal condition.
Meloxicam was excreted in the milk of lactating rats at
concentrations higher than those in plasma.
Females And Males Of Reproductive Potential
Based on the mechanism of action, the use of
prostaglandin-mediated NSAIDs, including VIVLODEX, may delay or prevent rupture
of ovarian follicles, which has been associated with reversible infertility in
some women. Published animal studies have shown that administration of
prostaglandin synthesis inhibitors has the potential to disrupt
prostaglandin-mediated follicular rupture required for ovulation. Small studies
in women treated with NSAIDs have also shown a reversible delay in ovulation.
Consider withdrawal of NSAIDs, including VIVLODEX, in women who have
difficulties conceiving or who are undergoing investigation of infertility.
The safety and effectiveness of VIVLODEX in pediatric
patients has not been established.
Elderly patients, compared to younger patients, are at
greater risk for NSAID-associated serious cardiovascular, gastrointestinal,
and/or renal adverse reactions. If the anticipated benefit for the elderly
patient outweighs these potential risks, start dosing at the low end of the
dosing range, and monitor patients for adverse effects [see WARNINGS AND PRECAUTIONS]. Of the total number
of patients in clinical studies of VIVLODEX, 291 were age 65 and over. 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.
No dose adjustment is necessary in patients with mild to
moderate hepatic impairment. Patients with severe hepatic impairment have not
been adequately studied. Because meloxicam is significantly metabolized in the
liver; use VIVLODEX in patients with severe hepatic impairment only if the
benefits are expected to outweigh the risks. If VIVLODEX is used in patients
with severe hepatic impairment, monitor patients for signs of worsening liver
function [see WARNINGS AND PRECAUTIONS,
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 VIVLODEX in subjects with severe renal impairment is not
recommended. In a previous study, the free Cmax plasma concentrations following
a single dose of meloxicam were higher in patients with renal failure on
chronic hemodialysis (1% free fraction) in comparison to healthy volunteers
(0.3% free fraction). Therefore, the maximum VIVLODEX dosage in this population
is 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 WARNINGS AND
PRECAUTIONS, CLINICAL PHARMACOLOGY].