WARNING AND CAUTIONS

5.

WARNINGS AND PRECAUTIONS •Serious and potentially fatal cardiovascular (CV) thrombotic events, myocardial infarction, and stroke.

Patients with known CV disease/risk factors may be at greater risk.

(5.1) •Serious gastrointestinal (GI) adverse events which can be fatal.

The risk is greater in patients with a prior history of ulcer disease or GI bleeding, and in patients at higher risk for GI events, especially the elderly.

(5.2) •Elevated liver enzymes, and rarely, severe hepatic reactions.

Discontinue use immediately if abnormal liver enzymes persist or worsen.

(5.3) •New onset or worsening of hypertension.

Blood pressure should be monitored closely during treatment.

(5.4) •Fluid retention and edema.

Should be used with caution in patients with fluid retention or heart failure.

(5.5) •Renal papillary necrosis and other renal injury with long-term use.

Use with caution in the elderly, those with impaired renal function, heart failure, liver dysfunction, and those taking diuretics, ACE-inhibitors, or angiotensin II antagonists.

The use of meloxicam in patients with severe renal impairment is not recommended (5.6) •Serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal and can occur without warning.

Discontinue meloxicam at first appearance of rash or skin reactions.

(5.8) 5.1 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.

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 [see Contraindications (4.2)].

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 (5.2)].

5.2 Gastrointestinal (GI) Effects – Risk of GI Ulceration, Bleeding, and Perforation NSAIDs, including meloxicam, 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 3-6 months, and in about 2-4% 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 meloxicam, 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 meloxicam therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected.

This should include discontinuation of meloxicam until a serious GI adverse event is ruled out.

For high-risk patients, consider alternate therapies that do not involve NSAIDs.

5.3 Hepatic Effects Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including meloxicam.

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 (6.1)] .

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 meloxicam.

If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue meloxicam [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

5.4 Hypertension NSAIDs, including meloxicam, 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 meloxicam, 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.

5.5 Congestive Heart Failure and Edema Fluid retention and edema have been observed in some patients taking NSAIDs.

Use meloxicam with caution in patients with fluid retention, hypertension, or heart failure.

5.6 Renal Effects Long-term administration of NSAIDs, including meloxicam, 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 meloxicam 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 meloxicam [see Dosage and Administration (2.1), Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

Use caution when initiating treatment with meloxicam in patients with considerable dehydration.

It is advisable to rehydrate patients first and then start therapy with meloxicam.

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 meloxicam.

Because some meloxicam metabolites are excreted by the kidney, monitor patients with significant renal impairment closely.

5.7 Anaphylactoid Reactions As with other NSAIDs, anaphylactoid reactions have occurred in patients without known prior exposure to meloxicam.

Meloxicam 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 (4.1) and Warnings and Precautions (5.12)].

Seek emergency help in cases where an anaphylactoid reaction occurs.

5.8 Adverse Skin Reactions NSAIDs, including meloxicam, 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.

5.9 Pregnancy Starting at 30 weeks gestation, avoid the use of meloxicam, because it may cause premature closure of the ductus arteriosus [see Use in Specific Populations (8.1) and Patient Counseling Information (17.8)].

5.10 Corticosteroid Treatment Meloxicam 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.

5.11 Masking of Inflammation and Fever The pharmacological activity of meloxicam in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.

5.12 Hematological Effects Anemia may occur in patients receiving NSAIDs, including meloxicam.

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 meloxicam, 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 meloxicam who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants.

5.13 Use in Patients with 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, meloxicam should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with pre-existing asthma.

5.14 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, meloxicam should be discontinued.